6,7-dihydro-5h-pyrazolo[5,1-b][1,3]oxazine-2-carboxamide compounds

ABSTRACT

The present invention is directed to PDE4B inhibitors of Formula I: (I) or a pharmaceutically acceptable salt thereof, wherein the substituents R 1 , R 2 , R 3 , and R 4  are as defined herein. The invention is also directed to pharmaceutical compositions comprising the compounds, methods of treatment using the compounds, and methods of preparing the compounds.

FIELD OF THE INVENTION

The present invention relates to6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine compounds of Formula I, whichare inhibitors of PDE4 isozymes, especially with a binding affinity forthe PDE4B isoform, and to the use of such compounds in methods fortreating central nervous system (CNS), metabolic, autoimmune andinflammatory diseases or disorders.

BACKGROUND OF THE INVENTION

Phosphodiesterases (PDEs) are a class of intracellular enzymes thathydrolyze the second messenger signaling molecules 3′,5′-cyclicadenosine monophosphate (cAMP) and guanosine 3′,5′-cyclic guanosinemonophosphate (cGMP) into the nonsignaling 5′-adenosine monophosphateand 5′-guanosine monophosphate, respectively.

cAMP functions as a second messenger regulating many intracellularprocesses within the body. One example is in the neurons of the centralnervous system, where the activation of cAMP-dependent kinases and thesubsequent phosphorylation of proteins are involved in acute regulationof synaptic transmission as well as neuronal differentiation andsurvival. The complexity of cyclic nucleotide signaling is indicated bythe molecular diversity of the enzymes involved in the synthesis anddegradation of cAMP. There are at least ten families of adenylylcyclases, and eleven families of phosphodiesterases. Furthermore,different types of neurons are known to express multiple isozymes ofeach of these classes, and there is good evidence forcompartmentalization and specificity of function for different isozymeswithin a given neuron.

A principal mechanism for regulating cyclic nucleotide signaling is viaphosphodiesterase-catalyzed cyclic nucleotide catabolism. The elevenknown families of PDEs are encoded by 21 different genes; each genetypically yields multiple splice variants that further contribute to theisozyme diversity. The PDE families are distinguished functionally basedon cyclic nucleotide substrate specificity, mechanism(s) of regulation,and sensitivity to inhibitors. Furthermore, PDEs are differentiallyexpressed throughout the organism, including in the central nervoussystem. As a result of these distinct enzymatic activities andlocalization, different PDEs' isozymes can serve distinct physiologicalfunctions. Furthermore, compounds that can selectively inhibit distinctPDE isozymes may offer particular therapeutic effects, fewer sideeffects, or both (Deninno, M., Future Directions in PhosphodiesteraseDrug Discovery. Bioorganic and Medicinal Chemistry Letters 2012, 22,6794-6800).

The present invention relates to compounds having a binding affinity forthe fourth family of PDEs (i.e., PDE4A, PDE4B, PDE4C, and PDE4D), and,in particular, a binding affinity for the PDE4A, PDE4B, and PDE4Cisoforms.

The PDE4 isozymes carry out selective, high-affinity hydrolyticdegradation of the second messenger adenosine 3′,5′-cyclic monophosphate(cAMP), and are characterized by sensitivity to inhibition by Rolipram™(Schering AG); beneficial pharmacological effects resulting from thatinhibition have been shown in a variety of disease models. A number ofother PDE4 inhibitors have been discovered in recent years. For example,Roflumilast (Daliresp®), marketed by AstraZenecais approved for severechronic obstructive pulmonary disease (COPD) to decrease the number offlare-ups or prevent exacerbations of COPD symptoms. Apremilast(Otezla®) has been approved by the U.S. Food and Drug Administration forthe treatment of adults with active psoriatic arthritis.

While beneficial pharmacological activity of PDE4 inhibitors has beenshown, a common side effect of these treatments has been the inductionof gastrointestinal symptoms such as nausea, emesis, and diarrhea, whichare hypothesized to be associated with inhibition of the PDE4D isoform.Attempts have been made to develop compounds with an affinity for thePDE4B isoform over the PDE4D isoform (See: Donnell, A. F. et al.,Identification of pyridazino[4,5-b]indolizines as selective PDE4Binhibitors. Bioorganic & Medicinal Chemistry Letters 2010, 20, 2163-7;and Naganuma, K. et al., Discovery of selective PDE4B inhibitors.Bioorganic and Medicinal Chemistry Letters 2009, 19, 3174-6). However,there remains a need to develop selective PDE4 inhibitors, especiallythose having an affinity for the PDE4B isoform. In particular, compoundswith enhanced binding affinity for the PDE4B isoform over the PDE4Disoform are anticipated to be useful in the treatment of variousdiseases and disorders of the central nervous system (CNS). Thediscovery of selected compounds of the present invention addresses thiscontinued need, and provides additional therapies for the treatment ofvarious diseases and disorders of the central nervous system (CNS), aswell as metabolic, autoimmune and inflammatory diseases or disorders.

Treatment with the PDE4B inhibitors of the present invention may alsolead to a decrease in gastrointestinal side effects (e.g., nausea,emesis and diarrhea) believed to be associated with inhibition of thePDE4D isoform (Robichaud, A. et al., Deletion of Phosphodiesterase 4D inMice Shortens □2-Adrenoreceptor-Mediated Anesthesia, A BehavioralCorrelate of Emesis. Journal of Clinical Investigation 2002, 110,1045-1052).

SUMMARY OF THE INVENTION

The present invention is directed to compounds of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is a substituent selected from the group consisting of(C₃-C₈)cycloalkyl, (4- to 10-membered)heterocycloalkyl, (C₈-C₁₀)aryl,and (5- to 10-membered)heteroaryl, wherein the (C₃-C₈)cycloalkyl, (4- to10-membered)heterocycloalkyl, (C₆-C₁₀)aryl and (5- to10-membered)heteroaryl are optionally substituted with one to five R⁵;

R² and R³ are each independently selected from the group consisting ofhydrogen, optionally substituted (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl, (4- to10-membered)heterocycloalkyl, (C₆-C₁₀)aryl, and (5- to10-membered)heteroaryl, wherein the (C₃-C₈)cycloalkyl, (4- to10-membered)heterocycloalkyl, (C₆-C₁₀)aryl, and (5- to10-membered)heteroaryl are optionally substituted with one to five R⁶;or

R² and R³ taken together with the nitrogen to which they are attachedform a (4- to 10-membered)heterocycloalkyl or a (5- to10-membered)heteroaryl, wherein the (4- to 10-membered)heterocycloalkyland (5- to 10-membered)heteroaryl are optionally substituted with one tofive R⁶;

when present, R⁴, at each occurrence, is independently selected from thegroup consisting of halogen, cyano, hydroxy, —SF₅, nitro, optionallysubstituted (C₁-C₆)alkyl, optionally substituted (C₂-C₆)alkenyl,optionally substituted (C₂-C₆)alkynyl, optionally substituted(C₁-C₆)alkylthio, optionally substituted (C₁-C₆)alkoxy, —N(R⁷)(R⁸),—N(R⁷)(C═(O)R⁸), —C(═O)N(R⁷)(R⁸), —O—C(═O)—N(R⁷)(R⁸), —C(═O)—R⁷, and—C(═O)—OR⁷;

when present, R⁵ and R⁶, at each occurrence, are independently selectedfrom the group consisting of halogen, oxo, cyano, hydroxy, —SF₅, nitro,optionally substituted (C₁-C₆)alkyl, optionally substituted(C₂-C₆)alkenyl, optionally substituted (C₂-C₆)alkynyl, optionallysubstituted (C₁-C₆)alkylthio, optionally substituted (C₁-C₆)alkoxy,—N(R⁷)(R⁸), —N(R⁷)(C═(O)R⁸), —C(═O)N(R⁷)(R⁸), —O—C(═O)—N(R⁷)(R⁸),—C(═O)—R⁷, and —C(═O)—OR⁷;

R⁷ and R⁸ at each occurrence are independently selected from the groupconsisting of hydrogen and (C₁-C₆)alkyl; and

a is represented by an integer selected from 0, 1, 2 or 3.

Compounds of the invention include Examples 1-64 or a pharmaceuticallyacceptable salt thereof as described herein.

The compounds of Formula I are inhibitors of the PDE4B isoform.

The compounds of Formula I are useful for treating or preventingdiseases and/or disorders of the central nervous system (CNS), pain,trauma, cardiologic, thrombotic, metabolic, autoimmune and inflammatorydiseases or disorders, and disorders associated with enhancedendothelial activity/impaired endothelial barrier function.

The present invention is also directed to the use of the compoundsdescribed herein, or a pharmaceutically acceptable salt thereof, in thepreparation of a medicament for the treatment or prevention of acondition amenable to modulation of the PDE4B gene family (i.e., PDE4Benzymes).

The present invention is also directed to pharmaceutically acceptableformulations containing an admixture of a compound(s) of the presentinvention and at least one excipient formulated into a pharmaceuticaldosage form. Examples of such dosage forms include tablets, capsules,suppositories, gels, creams, ointments, lotions, solutions/suspensionsfor injection (e.g., depot), aerosols for inhalation andsolutions/suspensions for oral ingestion.

DETAILED DESCRIPTION OF THE INVENTION

The headings within this document are being utilized only to expediteits review by the reader. They should not be construed as limiting theinvention or claims in any manner.

Definitions and Exemplifications

As used throughout this application, including the claims, the followingterms have the meanings defined below, unless specifically indicatedotherwise. The plural and singular should be treated as interchangeable,other than the indication of number:

As used herein, the term “n-membered” where n is an integer typicallydescribes the number of ring-forming atoms in a moiety where the numberof ring-forming atoms is n. For example, pyridine is an example of a6-membered heteroaryl ring and thiazole is an example of a 5-memberedheteroaryl group.

At various places in the present specification, substituents ofcompounds of the invention are disclosed in groups or in ranges. It isspecifically intended that the invention include each and everyindividual subcombination of the members of such groups and ranges. Forexample, the term “(C₁-C₆)alkyl” is specifically intended to include C₁alkyl (methyl), C₂ alkyl (ethyl), C₃ alkyl, C₄ alkyl, C₅ alkyl, and C₆alkyl. For another example, the term “a (5- to10-membered)heterocycloalkyl group” is specifically intended to includeany 5-, 6-, 7-, 8-, 9-, and 10-membered heterocycloalkyl group.

The term “(C₁-C₆)alkyl”, as used herein, refers to a saturated,branched- or straight-chain alkyl group containing from 1 to 6 carbonatoms, such as, but not limited to, methyl, ethyl, n-propyl, isopropyl,n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl,neopentyl, and n-hexyl.

The term “optionally substituted (C₁-C₆)alkyl”, as used herein, refersto a (C₁-C₆)alkyl as defined above, in which one or more hydrogen atomsare replaced by a substituent selected from the group consisting ofhalogen, oxo, cyano, hydroxy, —SF₅, nitro, —N(R⁷)(R⁸), —N(R⁷)(C(═O)R⁸),—N(R⁷)C(═O)—OR⁸, —C(═O)—N(R⁷)(R⁸), —O—C(═O)—N(R⁷)(R⁸), —C(═O)—R⁷,—C(═O)—OR⁷, and (C₃-C₈)cycloalkyl, in which R⁷ and R⁸ are eachindependently hydrogen or optionally substituted (C₁-C₆)alkyl. Forexample, a (C₁-C₆)alkyl moiety can be substituted with one or morehalogen atoms to form a “halo(C₁-C₆)alkyl”. Representative examples of ahalo(C₁-C₆)alkyl include, but are not limited to, fluoromethyl,2-fluoroethyl, difluoromethyl, trifluoromethyl, and pentafluoroethyl.

The term “(C₂-C₆)alkenyl” refers to an aliphatic hydrocarbon having from2 to 6 carbon atoms and having at least one carbon-carbon double bond,including straight chain or branched chain groups having at least onecarbon-carbon double bond. Representative examples include, but are notlimited to, ethenyl, 1-propenyl, 2-propenyl (allyl), isopropenyl,2-methyl-1-propenyl, 1-butenyl, 2-butenyl, and the like. When thecompounds of the invention contain a (C₂-C₆)alkenyl group, the compoundmay exist as the pure E (entgegen) form, the pure Z (zusammen) form, orany mixture thereof.

The term “optionally substituted (C₂-C₆)alkenyl” refers to a(C₂-C₆)alkenyl as defined above, in which one or more hydrogen atoms arereplaced by a substituent selected from the group consisting of halogen,oxo, cyano, hydroxy, —SF₅, nitro, —N(R⁷)(R⁸), —N(R⁷)(C(═O)R⁸),—N(R⁷)C(═O)—OR⁸, —C(═O)—N(R⁷)(R⁸), —O—C(═O)—N(R⁷)(R⁸), —C(═O)—R⁷,—C(═O)—OR⁷, and (C₃-C₈)cycloalkyl, in which R⁷ and R⁸ are eachindependently hydrogen or optionally substituted (C₁-C₆)alkyl.

The term “(C₂-C₆)alkynyl” refers to an aliphatic hydrocarbon having twoto six carbon atoms and at least one carbon-carbon triple bond,including straight chains and branched chains having at least onecarbon-carbon triple bond. Representative examples include, but are notlimited to, ethynyl, propynyl, butynyl, pentynyl, and hexynyl.

The term “optionally substituted (C₂-C₆)alkynyl” refers to a(C₂-C₆)alkynyl as defined above, in which one or more hydrogen atoms arereplaced by a substituent selected from the group consisting of halogen,oxo, cyano, hydroxy, —SF₅, —N(R⁷)(R⁸), —N(R⁷)(C(═O)R⁸), —N(R⁷)C(═O)—OR⁸,—C(═O)—N(R⁷)(R⁸), —O—C(═O)—N(R⁷)(R⁸), —C(═O)—R⁷, —C(═O)—OR⁷, and(C₃-C₈)cycloalkyl, in which R⁷ and R⁸ are each independently hydrogen oroptionally substituted (C₁-C₆)alkyl.

The term “(C₁-C₆)alkoxy” as used herein, refers to a (C₁-C₆)alkyl group,as defined above, attached to the parent molecular moiety through anoxygen atom. Representative examples of a (C₁-C₆)alkoxy include, but arenot limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy,tert-butoxy, pentyloxy, and hexyloxy.

The term “optionally substituted (C₁-C₆)alkoxy” as used herein, refersto a (C₁-C₆)alkoxy group, as defined above, in which one or morehydrogen atoms are replaced by a substituent selected from the groupconsisting of halogen, oxo, cyano, hydroxy, —SF₅, nitro, —N(R⁷)(R⁸),—N(R⁷)(C(═O)R⁸), —N(R⁷)C(═O)—OR⁸, —C(═O)—N(R⁷)(R⁸), —O—C(═O)—N(R⁷)(R⁸),—C(═O)—R⁷, —C(═O)—OR⁷, and (C₃-C₈)cycloalkyl, in which R⁷ and R⁸ areeach independently hydrogen or optionally substituted (C₁-C₆)alkyl. Forexample, a (C₁-C₆)alkoxy can be substituted with one or more halogenatoms to form a “halo(C₁-C₆)alkoxy”. Representative examples of ahalo(C₁-C₆)alkoxy include, but are not limited to, fluoromethoxy,difluoromethoxy, 2-fluoroethoxy, trifluoromethoxy, andpentafluoroethoxy.

The term “(C₁-C₆)alkythio”, as used herein, refers to a (C₁-C₆)alkylgroup, as defined above, attached to the parent molecular moiety througha sulfur atom. Representative examples of a (C₁-C₆)alkylthio include,but are not limited to, methylthio, ethylthio, propylthio, and the like.

The term “optionally substituted (C₁-C₆)alkythio”, as used herein,refers to a (C₁-C₆)alkylthio group, as defined above, in which one ormore hydrogen atoms are replaced by a substituent selected from thegroup consisting of halogen, oxo, cyano, hydroxy, —SF₅, nitro,—N(R⁷)(R⁸), —N(R⁷)(C(═O)R⁸), —N(R⁷)C(═O)—OR⁸, —C(═O)—N(R⁷)(R⁸),—O—C(═O)—N(R⁷)(R⁸), —C(═O)—R⁷, —C(═O)—OR⁷, and (C₃-C₈)cycloalkyl, inwhich R⁷ and R⁸ are each independently hydrogen or optionallysubstituted (C₁-C₆)alkyl.

As used herein, the term “(C₃-C₈)cycloalkyl” refers to a carbocyclicsubstituent obtained by removing hydrogen from a saturated carbocyclicmolecule wherein the cyclic framework has 3 to 8 carbons. A“(C₃-C₆)cycloalkyl” refers to a carbocyclic substituent obtained byremoving hydrogen from a saturated carbocyclic molecule having from 3 to6 carbon atoms. A “cycloalkyl’ may be a monocyclic ring, examples ofwhich include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, and cyclooctyl. Also included in the definition ofcycloalkyl are unsaturated non-aromatic cycloalkyls such as, but notlimited to, cyclohexenyl, cyclohexadienyl, cyclopentenyl, cycloheptenyl,and cyclooctenyl. Alternatively, a cycloalkyl may contain more than onering such as a “(C₄-C₈)bicycloalkyl”. The term “(C₄-C₈)bicycloalkyl”refers to a bicyclic ring system containing from 4 to 8 carbon atoms.The bicycloalkyl may be fused, such as bicyclo[1.1.0]butanyl,bicyclo[2.1.0]pentanyl, bicyclo[2.2.0]hexanyl, bicyclo[3.1.0]hexanyl,bicyclo[3.2.0]heptanyl, and bicyclo[3.3.0]-octanyl. The term“bicycloalkyl” also includes bridged bicycloalkyl systems such as, butnot limited to, bicyclo[2.2.1]heptanyl and bicyclo[1.1.1]pentanyl.

The term “optionally substituted “(C₃-C₈)cycloalkyl” refers to a(C₃-C₈)cycloalkyl, as defined above, in which one or more hydrogen atomsare replaced by a substituent selected from the group consisting ofhalogen, oxo, cyano, hydroxy, —SF₅, nitro, optionally substituted(C₁-C₆)alkyl, optionally substituted (C₁-C₆)alkoxy, optionallysubstituted (C₁-C₆)alkylthio, —N(R⁷)(R⁸), —N(R⁷)(C(═O)R⁸),—N(R⁷)C(═O)—OR⁸, —C(═O)—N(R⁷)(R⁸), —O—C(═O)—N(R⁷)(R⁸), —C(═O)—R⁷,—C(═O)—OR⁷, and (C₃-C₈)cycloalkyl, in which R⁷ and R⁸ are eachindependently hydrogen or optionally substituted (C₁-C₆)alkyl.

A “heterocycloalkyl,” as used herein, refers to a cycloalkyl as definedabove, wherein at least one of the ring carbon atoms is replaced with aheteroatom selected from nitrogen, oxygen or sulfur. The term “(4- to6-membered)heterocycloalkyl” means the heterocycloalkyl substituentcontains a total of 4 to 6 ring atoms, at least one of which is aheteroatom. The term “(4- to 8-membered)heterocycloalkyl” means theheterocycloalkyl substituent contains a total of 4 to 8 ring atoms, atleast one of which is a heteroatom. A “(4- to10-membered)heterocycloalkyl” means the heterocycloalkyl substituentcontains a total of 4 to 10 ring atoms. A “(6-membered)heterocycloalkyl”means the heterocycloalkyl substituent contains a total of 6 ring atoms,at least one of which is a heteroatom. A “(5-membered)heterocycloalkyl”means the heterocycloalkyl substituent contains a total of 5 ring atomsat least one of which is a heteroatom. A heterocycloalkyl may be asingle ring with up to 10 total members. Alternatively, aheterocycloalkyl as defined above may comprise 2 or 3 rings fusedtogether, wherein at least one such ring contains a heteroatom as a ringatom (i.e., nitrogen, oxygen, or sulfur). The heterocycloalkylsubstituent may be attached to the pyrazolooxazine core of the compoundsof the present invention via a nitrogen atom having the appropriatevalence, or via any ring carbon atom. The heterocycloalkyl substituentmay also be attached to the nitrogen of the amide moiety on thepyrazolooxazine core. The heterocycloalkyl moiety may be optionallysubstituted with one or more substituents at a nitrogen atom having theappropriate valence, or at any available carbon atom.

Also included in the definition of “heterocycloalkyl” areheterocycloalkyls that are fused to a phenyl or naphthyl ring or to aheteroaryl ring such as, but not limited to, a pyridinyl ring or apyrimidinyl ring.

Examples of heterocycloalkyl rings include, but are not limited to,azetidinyl, dihydrofuranyl, dihydrothiophenyl, tetrahydrothiophenyl,tetrahydrofuranyl, tetrahydrotriazinyl, tetrahydropyrazolyl,tetrahydrooxazinyl, tetrahydropyrimidinyl, octahydrobenzofuranyl,octahydrobenzimidazolyl, octahydrobenzothiazolyl, imidazolidinyl,pyrrolidinyl, piperidinyl, piperazinyl, oxazolidinyl, thiazolidinyl,pyrazolidinyl, thiomorpholinyl, tetrahydropyranyl, tetrahydrothiazinyl,tetrahydrothiadiazinyl, tetrahydro-oxazolyl, morpholinyl, oxetanyl,tetrahydrodiazinyl, oxazinyl, oxathiazinyl, quinuclidinyl, chromanyl,isochromanyl, dihydrobenzodioxinyl, benzodioxolyl, benzoxazinyl,indolinyl, dihydrobenzofuranyl, tetrahydroquinolyl, isochromyl,dihydro-1H-isoindolyl, 2-azabicyclo[2.2.1]heptanonyl,3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl and the like.Further examples of heterocycloalkyl rings include tetrahydrofuran-2-yl,tetrahydrofuran-3-yl, imidazolidin-1-yl, imidazolidin-2-yl,imidazolidin-4-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl,piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl,piperazin-1-yl, piperazin-2-yl, 1,3-oxazolidin-3-yl, 1,4-oxazepan-1-yl,isothiazolidinyl, 1,3-thiazolidin-3-yl, 1,2-pyrazolidin-2-yl,1,2-tetrahydrothiazin-2-yl, 1,3-thiazinan-3-yl,1,2-tetrahydrodiazin-2-yl, 1,3-tetrahydrodiazin-1-yl, 1,4-oxazin-4-yl,oxazolidinonyl, 2-oxo-piperidinyl (e.g., 2-oxo-piperidin-1-yl), and thelike.

The term “optionally substituted heterocycloalkyl” [e.g., optionallysubstituted (4- to 10-membered)heterocycloalkyl] refers to aheterocycloalkyl, as defined above, in which one or more hydrogen atoms,where chemically permissible, are replaced by a substituent selectedfrom the group consisting of halogen, oxo, cyano, hydroxy, —SF₅, nitro,optionally substituted (C₁-C₆)alkyl, optionally substituted(C₁-C₆)alkoxy, optionally substituted (C₁-C₆)alkylthio, —N(R⁷)(R⁸),—N(R⁷)(C(═O)R⁸), —N(R⁷)C(═O)—OR⁸, —C(═O)—N(R⁷)(R⁸), —O—C(═O)—N(R⁷)(R⁸),—C(═O)—R⁷, —C(═O)—OR⁷, and (C₃-C₈)cycloalkyl, in which R⁷ and R⁸ areeach independently hydrogen or optionally substituted (C₁-C₆)alkyl.

A “(C₆-C₁₀)aryl” refers to an all-carbon monocyclic or fused-ringpolycyclic aromatic group having a conjugated pi-electron systemcontaining from 6 to 10 carbon atoms, such as phenyl or naphthyl.

The term “optionally substituted (C₆-C₁₀)aryl” refers to a (C₆-C₁₀)aryl,as defined above, in which one or more hydrogen atoms are replaced by asubstituent selected from the group consisting of halogen, oxo, cyano,hydroxy, —SF₅, nitro, optionally substituted (C₁-C₆)alkyl, optionallysubstituted (C₁-C₆)alkoxy, optionally substituted (C₁-C₆)alkylthio,—N(R⁷)(R⁸), —N(R⁷)(C(═O)R⁸), —N(R⁷)C(═O)—OR⁸, —C(═O)—N(R⁷)(R⁸),—O—C(═O)—N(R⁷)(R⁸), —C(═O)—R⁷, —C(═O)—OR⁷, and (C₃-C₈)cycloalkyl, inwhich R⁷ and R⁸ are each independently hydrogen or optionallysubstituted (C₁-C₆)alkyl.

As used herein, the term “heteroaryl” refers to monocyclic or fused-ringpolycyclic aromatic heterocyclic groups with one or more heteroatom ringmembers (ring-forming atoms) each independently selected from oxygen(O), sulfur (S) and nitrogen (N) in at least one ring. A “(5- to14-membered)heteroaryl” ring refers to a heteroaryl ring having from 5to 14 ring atoms in which at least one of the ring atoms is a heteroatom(i.e., oxygen, nitrogen, or sulfur), with the remaining ring atoms beingindependently selected from the group consisting of carbon, oxygen,nitrogen, and sulfur. A “(5- to 10-membered)heteroaryl” ring refers to aheteroaryl ring having from 5 to 10 ring atoms in which at least one ofthe ring atoms is a heteroatom (i.e., oxygen, nitrogen, or sulfur), withthe remaining ring atoms being independently selected from the groupconsisting of carbon, oxygen, nitrogen, and sulfur. A “(5- to10-membered)nitrogen-containing heteroaryl” ring refers to a heteroarylnng having from 5 to 10 ring atoms in which at least one of the ringatoms is nitrogen, with the remaining ring atoms being independentlyselected from the group consisting of carbon and nitrogen. A “(5- to6-membered)heteroaryl” refers to a heteroaryl ring having from 5 to 6ring atoms in which at least one of the ring atoms is a heteroatom(i.e., oxygen, nitrogen, or sulfur), with the remaining ring atoms beingindependently selected from the group consisting of carbon, oxygen,nitrogen, and sulfur. A “(5- to 6-membered)nitrogen-containingheteroaryl” refers to a heteroaryl ring having from 5 to 6 ring atoms inwhich one of the heteroatoms in the ring is a nitrogen. A“(6-membered)nitrogen-containing heteroaryl” refers to a heteroaryl ringhaving 6 ring atoms in which one of the heteroatoms in the ring is anitrogen. A “(5-membered)nitrogen-containing heteroaryl” refers to aheteroaryl ring having 5 ring atoms in which one of the heteroatoms inthe ring is a nitrogen. A heteroaryl may consist of a single ring or 2or 3 fused rings. Examples of heteroaryls include, but are not limitedto, 6-membered ring substituents such as pyridinyl, pyrazinyl,pyrimidinyl and pyridazinyl; 5-membered heteroaryls such as triazolyl,imidazolyl, furanyl, isoxazolyl, isothiazolyl, 1,2,3-, 1,2,4, 1,2,5-, or1,3,4-oxadiazolyl, oxazolyl, thiophenyl, thiazolyl, isothiazolyl, andpyrazolyl; 6/5-membered fused ring substituents such as indolyl,indazolyl, benzofuranyl, benzimidazolyl, benzothienyl, benzoxadiazolyl,benzothiazolyl, isobenzothiofuranyl, benzothiofuranyl, benzisoxazolyl,benzoxazolyl, benzodioxolyl, furanopyridinyl, purinyl, imidazopyridinyl,imidazopyrimidinyl, pyrrolopyridinyl, pyrazolopyridinyl,pyrazolopyrimidinyl, thienopyridinyl, triazolopyrimidinyl,triazolopyridinyl (e.g., [1,2,4]triazolo[1,5-a]pyridin-2-yl), andanthranilyl; and 6/6-membered fused ring substituents such asquinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, oxochromanyl, and1,4-benzoxazinyl.

It is to be understood that the heteroaryl may be optionally fused to acycloalkyl group, or to a heterocycloalkyl group, as defined herein.

The heteroaryl substituent may be attached to the pyrazolooxazine coreof the compounds of the present invention via a nitrogen atom having theappropriate valence, or via any ring carbon atom or to the nitrogen ofthe amide moiety on the pyrazolooxazine core. The heteroaryl moiety maybe optionally substituted with one or more substituents at a nitrogenatom having the appropriate valence, or at any available carbon atom.

The terms “optionally substituted (5- to 14-membered)heteroaryl”,“optionally substituted (5- to 6-membered)heteroaryl” and “optionallysubstituted (5- to 6-membered)nitrogen-containing heteroaryl” refer to a(5- to 14-membered)heteroaryl, a (5- to 6-membered)heteroaryl, and a (5-to 6-membered)nitrogen-containing heteroaryl, as defined above, in whichone or more hydrogen atoms are replaced, where chemically permissible,by a substituent selected from the group consisting of halogen, oxo,cyano, hydroxy, —SF₅, nitro, optionally substituted (C₁-C₆)alkyl,optionally substituted (C₁-C₆)alkoxy, optionally substituted(C₁-C₆)alkylthio, —N(R⁷)(R⁸), —N(R⁷)(C(═O)R⁸), —N(R⁷)C(═O)—OR⁸,—C(═O)—N(R⁷)(R⁸), —O—C(═O)—N(R⁷)(R⁸), —C(═O)—R⁷, —C(═O)—OR⁷, and(C₃-C₈)cycloalkyl, in which R⁷ and R⁸ are each independently hydrogen oroptionally substituted (C₁-C₆)alkyl. The substituent can be attached tothe heteroaryl moiety at any available carbon atom or to a heteroatomwhen the heteroatom is nitrogen having the appropriate valence.

“halo” or “halogen”, as used herein, refers to a chlorine, fluorine,bromine, or iodine atom.

“hydroxy” or “hydroxyl”, as used herein, means an —OH group.

“cyano”, as used herein, means a —CN group, which also may be depicted:

“nitro”, as used herein, means an —NO₂ group.

“oxo”, as used herein, means a ═O moiety. When an oxo is substituted ona carbon atom, they together form a carbonyl moiety [—C(═O)—]. When anoxo is substituted on a sulfur atom, they together form a sulfoxidemoiety [—S(═O)—]; when two oxo groups are substituted on a sulfur atom,they together form a sulfonyl moiety [—S(═O)₂—].

“Optionally substituted”, as used herein, means that substitution isoptional and therefore includes both unsubstituted and substituted atomsand moieties. A “substituted” atom or moiety indicates that any hydrogenon the designated atom or moiety can be replaced with a selection fromthe indicated substituent group (up to and including that every hydrogenatom on the designated atom or moiety is replaced with a selection fromthe indicated substituent group), provided that the normal valency ofthe designated atom or moiety is not exceeded, and that the substitutionresults in a stable compound. For example, if a methyl group (i.e.,—CH₃) is optionally substituted, then up to 3 hydrogen atoms on thecarbon atom can be replaced with substituent groups.

As used herein, unless specified, the point of attachment of asubstituent can be from any suitable position of the substituent. Forexample, pyridinyl (or pyridyl) can be 2-pyridinyl (or pyridin-2-yl),3-pyridinyl (or pyridin-3-yl), or 4-pyridinyl (or pyridin-4-yl).

When a bond to a substituent is shown to cross a bond connecting twoatoms in a ring, then such substituent may be bonded to any of thering-forming atoms in that ring that are substitutable (i.e., bonded toone or more hydrogen atoms). For example, as shown in Formula I above,R⁴ may be bonded to any ring-forming atom of the tetrahydropyran ringthat is substitutable.

“Therapeutically effective amount” refers to that amount of the compoundbeing administered which will relieve to some extent one or more of thesymptoms of the disorder being treated.

“Patient” refers to warm-blooded animals such as, for example, pigs,cows, chickens, horses, guinea pigs, mice, rats, gerbils, cats, rabbits,dogs, monkeys, chimpanzees, and humans.

“Treating” or “treat”, as used herein, unless otherwise indicated, meansreversing, alleviating, inhibiting the progress of, or preventing thedisorder or condition to which such term applies, or one or moresymptoms of such disorder or condition. The term “treatment”, as usedherein, unless otherwise indicated, refers to the act of treating as“treating” is defined immediately above. The term “treating” alsoincludes adjuvant and neo-adjuvant treatment of a subject.

“Pharmaceutically acceptable” indicates that the substance orcomposition must be compatible, chemically and/or toxicologically, withthe other ingredients comprising a formulation, and/or the mammal beingtreated therewith.

“Isoform” means any of several different forms of the same protein.

“Isozyme” or “isoenzyme” means a closely related variant of an enzymethat differs in amino acid sequence but catalyzes the same chemicalreaction.

“Isomer” means “stereoisomer” and “geometric isomer” as defined below.

“Stereoisomer” refers to compounds that possess one or more chiralcenters, which may each exist in the R or S configuration. Stereoisomersinclude all diastereomeric, enantiomeric and epimeric forms as well asracemates and mixtures thereof.

“Geometric isomer” refers to compounds that may exist in cis, trans,anti, entgegen (E), and zusammen (Z) forms as well as mixtures thereof.

This specification uses the terms “substituent,” “radical,” and “group”interchangeably.

If substituents are described as being “independently selected” from agroup, each instance of a substituent is selected independent of anyother. Each substituent therefore may be identical to or different fromthe other substituent(s).

As used herein the term “Formula I” may be hereinafter referred to as a“compound(s) of the invention.” Such terms are also defined to includeall forms of the compound of the invention including hydrates, solvates,isomers, crystalline and non-crystalline forms, isomorphs, polymorphs,and metabolites thereof. For example, the compounds of the invention, orpharmaceutically acceptable salts thereof, may exist in unsolvated andsolvated forms. When the solvent or water is tightly bound, the complexwill have a well-defined stoichiometry independent of humidity. When,however, the solvent or water is weakly bound, as in channel solvatesand hygroscopic compounds, the water/solvent content will be dependenton humidity and drying conditions. In such cases, non-stoichiometry willbe the norm.

The compounds of the invention may exist as clathrates or othercomplexes. Included within the scope of the invention are complexes suchas clathrates, drug-host inclusion complexes wherein the drug and hostare present in stoichiometric or non-stoichiometric amounts. Alsoincluded are complexes of the compounds of the invention containing twoor more organic and/or inorganic components, which may be instoichiometric or non-stoichiometric amounts. The resulting complexesmay be ionized, partially ionized, or non-ionized. For a review of suchcomplexes, see J. Pharm. Sci., 64 (8), 1269-1288 by Haleblian (August1975).

Some of the compounds of the invention have asymmetric carbon atoms. Thecarbon-carbon bonds of the compounds of the invention may be depictedherein using a solid line (

), a solid wedge (

), or a dotted wedge (

). The use of a solid line to depict bonds to asymmetric carbon atoms ismeant to indicate that all possible stereoisomers (e.g., specificenantiomers, racemic mixtures, etc.) at that carbon atom are included.The use of either a solid or dotted wedge to depict bonds to asymmetriccarbon atoms is meant to indicate that the stereoisomer shown ispresent. When present in racemic compounds, solid and dotted wedges areused to define relative stereochemistry, rather than absolutestereochemistry. Racemic compounds possessing such indicated relativestereochemistry are marked with (+/−). Unless stated otherwise, it isintended that the compounds of the invention can exist as stereoisomers,which include cis and trans isomers, optical isomers such as R and Senantiomers, diastereomers, geometric isomers, rotational isomers,conformational isomers, atropisomers, and mixtures thereof (such asracemates and diastereomeric pairs). The compounds of the invention mayexhibit more than one type of isomerism. Also included are acid additionor base addition salts wherein the counterion is optically active, forexample, D-lactate or L-lysine, or racemic, for example, DL-tartrate orDL-arginine.

When any racemate crystallizes, crystals of two different types arepossible. The first type is the racemic compound (true racemate)referred to above wherein one homogeneous form of crystal is producedcontaining both enantiomers in equimolar amounts. The second type is theracemic mixture or conglomerate wherein two forms of crystal areproduced in equimolar amounts each comprising a single enantiomer.

The compounds of this invention may be used in the form of salts derivedfrom inorganic or organic acids. Depending on the particular compound, asalt of the compound may be advantageous due to one or more of thesalt's physical properties, such as enhanced pharmaceutical stability indiffering temperatures and humidities, or a desirable solubility inwater or oil. In some instances, a salt of a compound also may be usedas an aid in the isolation, purification, and/or resolution of thecompound.

Where a salt is intended to be administered to a patient (as opposed to,for example, being used in an in vitro context), the salt preferably ispharmaceutically acceptable. The term “pharmaceutically acceptable salt”refers to a salt prepared by combining a compound of the presentinvention with an acid whose anion, or a base whose cation, is generallyconsidered suitable for mammalian consumption. Pharmaceuticallyacceptable salts are particularly useful as products of the methods ofthe present invention because of their greater aqueous solubilityrelative to the parent compound.

Suitable pharmaceutically acceptable acid addition salts of thecompounds of the present invention when possible include those derivedfrom inorganic acids, such as, but not limited to, hydrochloric,hydrobromic, hydrofluoric, boric, fluoroboric, phosphoric,meta-phosphoric, nitric, carbonic, sulfonic, and sulfuric acids, andorganic acids such as acetic, benzenesulfonic, benzoic, citric,ethanesulfonic, fumaric, gluconic, glycolic, isothionic, lactic,lactobionic, maleic, malic, methanesulfonic, trifluoromethanesulfonic,succinic, toluenesulfonic, tartaric, and trifluoroacetic acids. Suitableorganic acids generally include but are not limited to aliphatic,cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic, andsulfonic classes of organic acids.

Specific examples of suitable organic acids include but are not limitedto acetate, trifluoroacetate, formate, propionate, succinate, glycolate,gluconate, digluconate, lactate, malate, tartrate, citrate, ascorbate,glucuronate, maleate, fumarate, pyruvate, aspartate, glutamate,benzoate, anthranilate, stearate, salicylate, p-hydroxybenzoate,phenylacetate, mandelate, embonate (pamoate), methanesulfonate,ethanesulfonate, benzenesulfonate, pantothenate, toluenesulfonate,2-hydroxyethanesulfonate, sufanilate, cyclohexylamino-ethansulfonate,algenic acid, β-hydroxybutyric acid, galactarate, galacturonate,adipate, alginate, butyrate, camphorate, camphorsulfonate,cyclopentanepropionate, dodecylsulfate, glycoheptanoate,glycerophosphate, heptanoate, hexanoate, nicotinate,2-naphthalene-sulfonate, oxalate, palmoate, pectinate,3-phenylpropionate, picrate, pivalate, thiocyanate, and undecanoate.

Furthermore, where the compounds of the invention carry an acidicmoiety, suitable pharmaceutically acceptable salts thereof may includealkali metal salts, e.g., sodium or potassium salts; alkaline earthmetal salts, e.g., calcium or magnesium salts; and salts formed withsuitable organic ligands, e.g., quaternary ammonium salts. In anotherembodiment, base salts are formed from bases which form non-toxic salts,including aluminum, arginine, benzathine, choline, diethylamine,diolamine, glycine, lysine, meglumine (N-methylglucamine), olamine,tromethamine and zinc salts.

Organic salts may be made from secondary, tertiary or quaternary aminesalts, such as tromethamine, diethylamine, N,N′-benzylethylenediamine,chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine, andprocaine. Basic nitrogen-containing groups may be quaternized withagents such as lower alkyl (C₁-C₆) halides (e.g., methyl, ethyl, propyl,and butyl chlorides, bromides, and iodides), dialkyl sulfates (e.g.,dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain halides(e.g., decyl, lauryl, myristyl, and stearyl chlorides, bromides, andiodides), arylalkyl halides (e.g., benzyl and phenethyl bromides), andothers.

In one embodiment, hemisalts of acids and bases may also be formed, forexample, hemisulfate and hemicalcium salts.

Certain compounds of the invention may exist as geometric isomers. Thecompounds of the invention may possess one or more asymmetric centers,thus existing as two, or more, stereoisomeric forms. The presentinvention includes all the individual stereoisomers and geometricisomers of the compounds of the invention and mixtures thereof.Individual enantiomers can be obtained by chiral separation or using therelevant enantiomer in the synthesis.

In addition, the compounds of the present invention can exist inunsolvated as well as solvated forms with pharmaceutically acceptablesolvents such as water, ethanol and the like. In general, the solvatedforms are considered equivalent to the unsolvated forms for the purposesof the present invention. The compounds may also exist in one or morecrystalline states, i.e., polymorphs, or they may exist as amorphoussolids. All such forms are encompassed by the claims.

Also within the scope of the present invention are so-called “prodrugs”of the compound of the invention. Thus, certain derivatives of thecompound of the invention that may have little or no pharmacologicalactivity themselves can, when administered into or onto the body, beconverted into the compound of the invention having the desiredactivity, for example, by hydrolytic cleavage. Such derivatives arereferred to as “prodrugs.” Further information on the use of prodrugsmay be found in “Pro-drugs as Novel Delivery Systems, Vol. 14, ACSSymposium Series (T. Higuchi and W. Stella) and “Bioreversible Carriersin Drug Design,” Pergamon Press, 1987 (ed. E. B. Roche, AmericanPharmaceutical Association). Prodrugs in accordance with the inventioncan, for example, be produced by replacing appropriate functionalitiespresent in the compounds of the present invention with certain moietiesknown to those skilled in the art as “pro-moieties” as described, forexample, in “Design of Prodrugs” by H. Bundgaard (Elsevier, 1985).

This invention also encompasses compounds of the invention containingprotective groups. One skilled in the art will also appreciate thatcompounds of the invention can also be prepared with certain protectinggroups that are useful for purification or storage and can be removedbefore administration to a patient. The protection and deprotection offunctional groups is described in “Protective Groups in OrganicChemistry”, edited by J. F. W. McOmie, Plenum Press (1973) and“Protective Groups in Organic Synthesis”, 3rd edition, T. W. Greene andP. G. M. Wuts, Wiley-Interscience (1999).

The present invention also includes all pharmaceutically acceptableisotopically labeled compounds, which are identical to those recitedherein, wherein one or more atoms are replaced by an atom having thesame atomic number, but an atomic mass or mass number different from theatomic mass or mass number which predominates in nature. Examples ofisotopes suitable for inclusion in the compounds of the presentinvention include, but are not limited to, isotopes of hydrogen, such as²H, ³H; carbon, such as ¹¹C, ¹³C, and ¹⁴C; chlorine, such as ³⁶Cl;fluorine, such as ¹⁸F; iodine, such as ¹²³I and ¹²⁵I; nitrogen, such as¹³N and ¹⁵N; oxygen, such as ¹⁵O, ¹⁷O, and ¹³O; phosphorus, such as ³²P;and sulfur, such as ³⁵S. Certain isotopically-labeled compounds of thepresent invention, for example, those incorporating a radioactiveisotope, are useful in drug and/or substrate tissue distribution studies(e.g., assays). The radioactive isotopes tritium, i.e., ³H, andcarbon-14, i.e., ¹⁴C, are particularly useful for this purpose in viewof their ease of incorporation and ready means of detection.Substitution with heavier isotopes such as deuterium, i.e., ²H, mayafford certain therapeutic advantages resulting from greater metabolicstability, for example, increased in vivo half-life or reduced dosagerequirements and, hence, may be preferred in some circumstances.Substitution with positron-emitting isotopes, such as 11C, ¹⁵F, ¹⁸F, ¹⁵Oand ¹³N, can be useful in positron emission tomography (PET) studies forexamining substrate receptor occupancy. Isotopically labeled compoundsof the present invention can generally be prepared by conventionaltechniques known to those skilled in the art or by processes analogousto those described in the accompanying Schemes and/or in the Examplesand Preparations using an appropriate isotopically labeled reagent inplace of the non-labeled reagent previously employed. Pharmaceuticallyacceptable solvates in accordance with the invention include thosewherein the solvent of crystallization may be isotopically substituted,e.g., D₂O, acetone-d₆, or DMSO-d₆. Compounds of the invention, whichinclude compounds exemplified in Examples 1-104 described below, includeisotopically labeled versions of these compounds, such as, but notlimited to, the deuterated and tritiated isotopes and all other isotopesdiscussed above.

Compounds

The compounds of Formula I, as described above, contain a6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine core wherein the core issubstituted at the 3-position by an R¹ moiety that is optionallysubstituted with one to three R⁵; optionally substituted at the 5-, 6-and/or 7-positions by an R⁴ moiety; and the nitrogen of the amide moietyattached to the 2-position of the6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine core is substituted with R²and R³.

In one embodiment, in Formula I as described above, R¹ is an optionallysubstituted (C₃-C₈)cycloalkyl. When R¹ is an optionally substituted(C₃-C₈)cycloalkyl, the cycloalkyl is selected from the group consistingof cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

In another embodiment, in Formula I as described above, R¹ is anoptionally substituted (4- to 10-membered)heterocycloalkyl. When R¹ isan optionally substituted (4- to 10-membered)heterocycloalkyl, theheterocycloalkyl is selected from the group consisting of azetidinyl,dihydrofuranyl, dihydrothiophenyl, tetrahydrothiophenyl,tetrahydrofuranyl, tetrahydrotriazinyl, tetrahydropyrazolyl,tetrahydrooxazinyl, tetrahydropyrimidinyl, octahydrobenzofuranyl,octahydrobenzimidazolyl, octaohydrobenzothiazolyl, imidazolidinyl,pyrrolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isothiazolidinyl,thiazolidinyl, pyrazolidinyl, thiomorpholinyl, tetrahydropyranyl,tetrahydrothiazinyl, tetrahydrothiadiazinyl, tetrahydrooxazolyl,morpholinyl, oxetanyl, tetrahydrodiazinyl, dihydrooxazinyl,oxathiazinyl, quinuclidinyl, chromanyl, isochromanyl,dihydrobenzodioxinyl, benzodioxolyl, benzoxazinyl, indolinyl,dihydrobenzofuranyl, tetrahydroquinolyl, isochromanyl,dihydro-1H-isoindolyl, 2-azabicyclo[2.2.1]heptanonyl,3-azabicyclo[3.1.0]hexanyl, and 3-azabicyclo[4.1.0]heptanyl.

In another embodiment, in Formula I as described above, R¹ is anoptionally substituted (C₆-C₁₀)aryl selected from phenyl or naphthyl.

In certain other embodiments, when R¹ is an optionally substituted(C₆-C₁₀)aryl, the aryl is phenyl.

In another embodiment, in Formula I as described above, R¹ is anoptionally substituted (5- to 10-membered)heteroaryl.

In certain embodiments, R¹ is an optionally substituted (5- to10-membered) heteroaryl.

In certain other embodiments, R¹ is an optionally substituted (5- to6-membered) heteroaryl.

In certain embodiments, when R¹ is an optionally substituted (5- to10-membered)heteroaryl, the heteroaryl is selected from the groupconsisting of triazolyl, imidazolyl, furanyl, isoxazolyl, isothiazolyl,1,2,3-, 1,2,4, 1,2,5-, or 1,3,4-oxadiazolyl, oxazolyl, thiophenyl,thiazolyl, isothiazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl,pyridazinyl, indolyl, indazolyl, benzofuranyl, benzimidazolyl,benzothienyl, benzoxadiazolyl, benzothiazolyl, isobenzothiofuranyl,benzothiofuranyl, benzisoxazolyl, benzoxazolyl, benzodioxolyl,furanopyridinyl, purinyl, imidazopyridinyl, im idazopyrimidinyl,pyrrolopyridinyl, pyrazolopyridinyl, pyrazolopyrimidinyl,thienopyridinyl, triazolopyrimidinyl, triazolopyridinyl, quinolinyl,isoquinolinyl, cinnolinyl, quinazolinyl, oxochromenyl, and1,4-benzoxazinyl.

In certain other embodiments, when R¹ is an optionally substituted (5-to 10-membered) heteroaryl, the heteroaryl is selected from the groupconsisting of pyridinyl, triazolopyridinyl, pyrazolopyridinyl, andbenzooxazolyl.

In certain embodiments, when R¹ is an optionally substituted (5- to6-membered)heteroaryl the heteroaryl is a(5-membered)nitrogen-containing heteroaryl. For example, the(5-membered)nitrogen-containing heteroaryl is selected from the groupconsisting of pyrazolyl, imidazolyl, and triazolyl.

In certain embodiments, when R¹ is an optionally substituted (5- to6-membered)heteroaryl the heteroaryl is a(6-membered)nitrogen-containing heteroaryl. For example, the(6-membered)nitrogen-containing heteroaryl is selected from the groupconsisting of pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl. Incertain embodiments, the (6-membered)nitrogen-containing heteroaryl ispyridinyl.

In any of the preceding embodiments, where chemically permissible, R¹ isoptionally substituted with one to three R⁵, and each R⁵ isindependently selected from the group consisting of halogen, cyano,optionally substituted (C₁-C₆)alkyl, and optionally substituted(C₁-C₆)alkoxy.

In certain embodiments, R⁵ is a halogen selected from fluoro or chloro.

In certain other embodiments, R⁵ is an optionally substituted(C₁-C₆)alkyl, and the alkyl is selected from methyl, ethyl or propyl,and the methyl, ethyl and propyl are optionally substituted with one tothree fluorine atoms. For example, an optionally substituted alkylincludes, but is not limited to, fluoromethyl, difluoromethyl,trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, and thelike.

In yet another embodiment, R⁵ is an optionally substituted(C₁-C₆)alkoxy, and the alkoxy is selected from methoxy, ethoxy orpropoxy and the methoxy, ethoxy and propoxy are optionally substitutedwith one to three fluorine atoms. For example, an optionally substitutedalkoxy includes, but is not limited to, fluoromethoxy, difluoromethoxy,trifluoromethoxy, fluoroethoxy, difluoroethoxy, trifluoroethoxy, and thelike.

It is to be understood that any of the above-mentioned subgenuses of R¹can be combined together with any of the embodiments for R², R³ and R⁴as described above and hereinafter.

In another embodiment, in Formula I as described above, R² and R³ areeach independently selected from the group consisting of hydrogen,optionally substituted (C₁-C₆)alkyl, (C₃-C₃)cycloalkyl, and (5- to6-membered)heteroaryl, and where chemically permissible, the(C₃-C₈)cycloalkyl, and (5- to 6-membered)heteroaryl are optionallysubstituted with one to three R⁶.

In certain embodiments, in Formula I as described above, one of R² andR³ is hydrogen and the other is an optionally substituted (C₁-C₆)alkyl.

In certain embodiments, when one of R² and R³ is an optionallysubstituted (C₁-C₆)alkyl, the alkyl is selected from the groupconsisting of methyl, ethyl, propyl, isopropyl, butyl, tert-butyl,pentyl and hexyl.

In certain embodiments, when one of R² and R³ is an optionallysubstituted (C₁-C₆)alkyl, the alkyl is selected from the groupconsisting of methyl, ethyl, propyl, and isopropyl.

In another embodiment, in Formula I as described above; one of R² and R³is hydrogen and the other is (C₃-C₈)cycloalkyl, wherein the cycloalkylis optionally substituted with one to three R⁶.

In certain embodiments, when one of R² and R³ is an optionallysubstituted (C₃-C₈)cycloalkyl, the cycloalkyl is selected fromcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl orbicyclo[1.1.1]pentyl.

In certain embodiments, when one of R² and R³ is an optionallysubstituted (C₃-C₈)cycloalkyl, the cycloalkyl is selected fromcyclopropyl, cyclobutyl, and cyclopentyl.

In certain embodiments, when one of R² and R³ is an optionallysubstituted (C₃-C₈)cycloalkyl, the cycloalkyl is cyclopropyl.

In another embodiment, in Formula I as described above; one of R² and R³is hydrogen and the other is (5- to 6-membered)heteroaryl, wherein theheteroaryl is optionally substituted with one to three R⁶.

In certain embodiments, when one of R² and R³ is an optionallysubstituted (5- to 6-membered)heteroaryl, the heteroaryl is selectedfrom triazolyl, imidazolyl, furanyl, isoxazolyl, isothiazolyl, 1,2,3-,1,2,4, 1,2,5-, or 1,3,4-oxadiazolyl, oxazolyl, thiophenyl, thiazolyl,isothiazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, orpyridazinyl.

In certain embodiments, when one of R² and R³ is an optionallysubstituted (5- to 6-membered)heteroaryl, the heteroaryl is a (5- to6-membered)nitrogen-containing heteroaryl.

In certain embodiments, when one of R² and R³ is an optionallysubstituted (5- to 6-membered)nitrogen-containing heteroaryl, theheteroaryl is selected from triazolyl, imidazolyl, pyrazolyl, pyridinyl,pyrazinyl, pyrimidinyl, or pyridazinyl.

In certain embodiments, when one of R² and R³ is an optionallysubstituted (5- to 6-membered)nitrogen-containing heteroaryl, theheteroaryl is selected from triazolyl, pyrazolyl, or pyrimidinyl.

In another embodiment, in Formula I as described above, R² and R³ takentogether with the nitrogen to which they are attached form a (4- to6-membered)heterocycloalkyl optionally substituted with one to three R⁶.

In certain embodiments, when R² and R³ taken together with the nitrogento which they are attached form a (4- to 6-membered)heterocycloalkyl,the heterocycloalkyl is selected from the group consisting ofazetidinyl, tetrahydropyrazolyl, tetrahydrooxazinyl,tetrahydropyrimidinyl, imidazolidinyl, piperidinyl, piperazinyl,oxazolidinyl, and pyrrolidinyl.

In certain embodiments, when R² and R³ taken together with the nitrogento which they are attached form a (4-to 6-membered)heterocycloalkyl, theheterocycloalkyl is azetidinyl.

In any of the preceding embodiments, when one of R² and R³ is a(C₃-C₈)cycloalkyl, or (5- to 6-membered)heteroaryl substituted with oneto three R⁶, or R² and R³ taken together with the nitrogen to which theyare attached form a (4- to 6-membered)heterocycloalkyl optionallysubstituted with one to three R⁶, R⁶ at each occurrence is independentlyselected from the group consisting of halogen, oxo, cyano, hydroxy,optionally substituted (C₁-C₆)alkyl, and optionally substituted(C₁-C₆)alkoxy.

In certain embodiments, when R⁶ is a halogen, the halogen is selectedfrom fluoro and chloro.

In certain other embodiments, when R⁶ is an optionally substituted(C₁-C₆)alkyl, the alkyl is selected from methyl, ethyl or propyl, andthe methyl, ethyl and propyl are optionally substituted with one tothree fluorine atoms. For example, an optionally substituted alkylincludes, but is not limited to, fluoromethyl, difluoromethyl,trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, and thelike.

In yet another embodiment, when R⁶ is an optionally substituted(C₁-C₆)alkoxy, the alkoxy is selected from methoxy, ethoxy or propoxyand the methoxy, ethoxy and propoxy are optionally substituted with oneto three fluorine atoms. For example, an optionally substituted alkoxyincludes, but is not limited to, fluoromethoxy, difluoromethoxy,trifluoromethoxy, fluoroethoxy, difluoroethoxy, trifluoroethoxy, and thelike.

It is to be understood that any of the above-mentioned subgenuses of R²and R³ can be combined together with any of the embodiments as describedabove and hereinafter.

In another embodiment, in Formula I as described above, each R⁴, whenpresent, is independently selected from the group consisting of halogen,cyano, hydroxy, —SF₅, nitro, optionally substituted (C₁-C₆)alkyl, andoptionally substituted (C₁-C₆)alkoxy.

In certain embodiments, when R⁴ is halogen, the halogen is selected fromfluoro or chloro.

In certain other embodiments, when R⁴ is an optionally substituted(C₁-C₆)alkyl and/or an optionally substituted (C₁-C₆)alkoxy, the(C₁-C₆)alkyl and (C₁-C₆)alkoxy are as described above in any of thepreceding embodiments.

It is to be understood that any of the above-mentioned subgenuses of R⁴can be combined together with any of the embodiments for R¹, R² and R³as described above.

In another embodiment, in Formula I as described above in any of thepreceding embodiments, a is an integer selected from 0, 1 or 2. Incertain embodiments, a is 0. In certain other embodiments, a is 1. Incertain other embodiments, a is 2.

In certain other embodiments, the present invention is directed to acompound of Formula II:

or a pharmaceutically acceptable salt thereof, wherein:

R² and R³ are each independently selected from the group consisting ofhydrogen, optionally substituted (C₁-C₆)alkyl, and (C₃-C₈)cycloalkyl,wherein the (C₃-C₈)cycloalkyl is optionally substituted with one tothree R⁶; or

R² and R³ taken together with the nitrogen to which they are attachedform a (4- to 6-membered)heterocycloalkyl optionally substituted withone to three R⁶;

when present, each R⁴ is independently selected from halogen oroptionally substituted (C₁-C₆)alkyl;

when present, R⁵ and R⁶, at each occurrence, are independently selectedfrom the group consisting of halogen, cyano, optionally substituted(C₁-C₆)alkyl, and optionally substituted (C₁-C₆)alkoxy; and

a is an integer selected from 0, 1, or 2.

In certain embodiments, in Formula II as described above, one of R² andR³ is hydrogen and the other is an optionally substituted (C₁-C₆)alkyl.For example, the (C₁-C₆)alkyl can be selected from the group consistingof methyl, ethyl, propyl, and isopropyl.

In certain other embodiments, in Formula II as described above, one ofR² and R³ is hydrogen and the other is a (C₃-C₈)cycloalkyl optionallysubstituted with one to three R⁶. For example, the (C₃-C₈)cycloalkyl canbe selected from the group consisting of cyclopropyl, cyclobutyl, andcyclopentyl. In certain embodiments, the (C₃-C₈)cycloalkyl iscyclopropyl.

In certain embodiments, in Formula II as described above, R² and R³taken together with the nitrogen to which they are attached form a (4-to 6-membered)heterocycloalkyl optionally substituted with one to threeR⁶. For example, the (4- to 6-membered)heterocycloalkyl is azetidinyl.

In another embodiment, selected compounds of the present invention maybe useful for treating a PDE4B-mediated disorder, comprisingadministering to a mammal (preferably a human) in need thereof atherapeutically effective amount of a compound of the inventioneffective in inhibiting PDE4B activity; more preferably, administeringan amount of a compound of the invention having improved bindingaffinity for PDE4B while at the same time possessing less inhibitoryactivity toward PDE4D.

In certain other embodiments, selected compounds of the presentinvention may exhibit a binding affinity for the PDE4B isoform.

In certain embodiments, the compounds of the present invention have anenhanced binding affinity for the PDE4B isoform over the PDE4D isoformsuch that the compounds display about a 2-fold to about a 550-foldbinding affinity for the PDE4B isoform over the PDE4D isoform. Incertain other embodiments, the compounds of the present inventiondisplay about a 2-fold to about a 10-fold binding affinity for the PDE4Bisoform over the PDE4D isoform. In certain other embodiments, thecompounds of the present invention display about a 11-fold to about a30-fold binding affinity for the PDE4B isoform over the PDE4D isoform.In certain other embodiments, the compounds of the present inventiondisplay about a 31-fold to about a 90-fold binding affinity for thePDE4B isoform over the PDE4D isoform. In certain other embodiments, thecompounds of the present invention display about a 91-fold to about a125-fold binding affinity for the PDE4B isoform over the PDE4D isoform.In certain other embodiments, the compounds of the present inventiondisplay about a 126-fold to about a 225-fold binding affinity for thePDE4B isoform over the PDE4D isoform. In certain other embodiments, thecompounds of the present invention display about a 226-fold to about a350-fold binding affinity for the PDE4B isoform over the PDE4D isoform.In certain other embodiments, the compounds of the present inventiondisplay about a 351-fold to about a 550-fold binding affinity for thePDE4B isoform over the PDE4D isoform. In certain embodiments, thecompounds of the present invention display at least about a 5-foldbinding affinity for the PDE4B isoform over the PDE4D isoform. Incertain embodiments, the compounds of the present invention display atleast about a 10-fold binding affinity for the PDE4B isoform over thePDE4D isoform. In certain embodiments, the compounds of the presentinvention display at least about a 20-fold binding affinity for thePDE4B isoform over the PDE4D isoform. In certain other embodiments, thecompounds of the present invention display at least about a 40-foldbinding affinity for the PDE4B isoform over the PDE4D isoform. Incertain other embodiments, the compounds of the present inventiondisplay at least about a 50-fold binding affinity for the PDE4B isoformover the PDE4D isoform. In certain other embodiments, the compounds ofthe present invention display at least about a 75-fold binding affinityfor the PDE4B isoform over the PDE4D isoform. In certain otherembodiments, the compounds of the present invention display at leastabout a 100-fold binding affinity for the PDE4B isoform over the PDE4Disoform. In certain other embodiments, the compounds of the presentinvention display at least about a 200-fold binding affinity for thePDE4B isoform over the PDE4D isoform. In certain other embodiments, thecompounds of the present invention display at least about a 300-foldbinding affinity for the PDE4B isoform over the PDE4D isoform. Incertain other embodiments, the compounds of the present inventiondisplay up to about a 550-fold binding affinity for the PDE4B isoformover the PDE4D isoform. The binding affinities of the compounds of thepresent invention for the PDE4B and PDE4D isoforms are shown in Table 9of the Experimental Section below.

In another embodiment, the present invention provides a pharmaceuticalcomposition comprising a compound of the present invention, or apharmaceutically acceptable salt thereof, in admixture with at least onepharmaceutically acceptable excipient.

In yet another embodiment, administration of the compounds of thepresent invention to a patient in need thereof may also lead to adecrease in gastrointestinal discomfort such as emesis, diarrhea, andnausea, which is currently believed to be associated with administrationof compounds having binding affinity for other PDE4 isoforms, especiallythe PDE4D isoform, resulting in an increase in patient compliance aswell as overall treatment outcome.

In another embodiment, the present invention provides a method oftreating central nervous system (CNS), neuroinflammatory, metabolic,autoimmune and inflammatory diseases or disorders comprisingadministering to the mammal, particularly a human, in need of suchtreatment a therapeutically effect amount of a compound of the presentinvention, or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides the use of acompound of the present invention, or a pharmaceutically acceptable saltthereof, in the manufacture of a medicament for treating central nervoussystem (CNS), neuroinflammatory, autoimmune and inflammatory diseases ordisorders.

Pharmacology

Phosphodiesterases (PDEs) of the PDE4 family are characterized byselective, high-affinity hydrolytic degradation of the second messengercyclic nucleotide, adenosine 3′,5′-cyclic monophosphate (cAMP). ThePDE4A, PDE4B and PDE4D subtypes are known to be widely expressedthroughout the brain, with regional and intracellular distribution forthe PDE4A, PDE4B and PDE4D subtypes being distinct, whereas the PDE4Csubtype is expressed at lower levels throughout the central nervoussystem (See: Siuciak, J. A. et al., Antipsychotic profile of rolipram:efficacy in rats and reduced sensitivity in mice deficient in thephosphodiesterase-4B (PDE4B) enzyme, Psychopharmacology (2007)192:415-424). The location of the PDE4 subtypes makes them aninteresting target for exploring new treatments for central nervoussystem diseases and disorders. For example, PDE4B has been identified asa genetic susceptibility factor for schizophrenia (See: Millar, J. K. etal., Disrupted in schizophrenia 1 and phosphodiesterase 4B: towards anunderstanding of psychiatric illness, J. Physiol. 584 (2007) pp.401-405).

The PDE4 inhibitor rolipram has been shown to be useful in treating orreversing A13-induced memory deficits via the attenuation of neuronalinflammation and apoptosis-mediated cAMP/CREB signaling; thus PDE4 is apotential target for treatment of cognitive deficits associated with AD.(See: Wang, C. et al., The phosphodiesterase-4 inhibitor rolipramreverses Aβ-induced cognitive impairment and neuroinflammatory andapoptotic responses in rats, International Journal ofNeuropsychopharmacology (2012), 15, 749-766).

PDE4 inhibitors may also possess antidepressant effects by normalizingthe cAMP cascade (See: Fujita, M. et al., Downregulation of BrainPhosphodiesterase Type IV Measured with ¹¹ C-(R)-Rolipram PositronEmission Tomography in Major Depressive Disorder, Biological Psychiatry,72, 2012, 548-554).

Furthermore, PDE4 inhibitors have been shown to possess therapeuticactivity with implications for the treatment of multiple sclerosis (See:Sun, X. et al., Rolipram promotes remyelination possibly via MEK-ERKsignal pathway in cuprizone-induced demyelination mouse, ExperimentalNeurology 2012; 237:304-311).

In view of the above, in certain embodiments, the compounds of thepresent invention have a wide range of therapeutic applications for thetreatment of conditions or diseases of the central nervous system whichinclude neurologic, neurodegenerative and/or psychiatric disorders.Neurologic, neurodegenerative and/or psychiatric disorders include butare not limited to, (1) mood [affective] disorders; (2) neurotic,stress-related and somatoform disorders including anxiety disorders; (3)disorders comprising the symptom of cognitive deficiency in a mammal,including a human; (4) disorders comprising attention deficits,executive function deficits (working memory deficits), dysfunction ofimpulse control, extrapyramidal symptoms, disorders that are based on amalfunction of basal ganglia; (5) behavioral and emotional disorderswith onset usually occurring in childhood and adolescence; (6) disordersof psychological development; (7) systemic atrophies primarily affectingthe central nervous system; (8) extrapyramidal and movement disorders;(9) behavioral syndromes associated with physiological disturbances andphysical factors; (10) disorders of adult personality and behavior; (11)schizophrenia and other psychotic disorders; (12) mental and behavioraldisorders due to psychoactive substance use; (13) sexual dysfunctioncomprising excessive sexual drive; (14) mental retardation; (15)factitious disorders, e.g., acute hallucinatory mania; (16) episodic andparoxysmal disorders, epilepsy; (17) narcolepsy;

(18) dementia, and (19) amyotrophic lateral sclerosis.

Examples of mood [affective] disorders that can be treated according tothe present invention include, but are not limited to, bipolar disorderI, hypomania (manic and mixed form), bipolar disorder II; depressivedisorders such as single depressive episode or recurrent majordepressive disorder, chronic depression, psychotic depression, minordepressive disorder, depressive disorder with postpartum onset,depressive disorders with psychotic symptoms; persistent mood[affective] disorders such as cyclothymia, dysthymia, euthymia;premenstrual syndrome (PMS) and premenstrual dysphoric disorder.

Examples of neurotic, stress-related and somatoform disorders that canbe treated according to the present invention include, but are notlimited to, anxiety disorders, social anxiety disorder, general anxietydisorder, panic disorder with or without agoraphobia, specific phobia,social phobia, chronic anxiety disorders; obsessive compulsive disorder;reaction to severe stress and adjustment disorders, such aspost-traumatic stress disorder (PTSD), acute stress disorder; otherneurotic disorders such as depersonalization-derealization syndrome.

The phrase “cognitive deficiency” as used here in “disorders comprisingthe symptom of cognitive deficiency” refers to a subnormal functioningor a suboptimal functioning in one or more cognitive aspects such asmemory, intellect, learning and logic ability, or attention andexecutive function (working memory) in a particular individualcomparative to other individuals within the same general age population.

Examples of “disorders comprising the symptom of cognitive deficiency”that can be treated according to the present invention include, but arenot limited to, cognitive deficits primarily but not exclusively relatedto amnesia, psychosis (schizophrenia), Parkinson's disease, Alzheimer'sdisease, multi-infarct dementia, senile dementia, Lewis body dementia,stroke, frontotemporal dementia, progressive supranuclear palsy,Huntington's disease, HIV disease (HIV-associated dementia), cerebraltrauma and drug abuse; mild cognitive disorder ADHD, Asperger'ssyndrome, and age-associated memory impairment; cognitive decline ordelerium post-operative or in association with intensive care therapy.

Examples of disorders usually first diagnosed in infancy, childhood andadolescence that can be treated according to the present inventioninclude, but are not limited to, hyperkinetic disorders includingdisturbance of activity and attention, attention deficit/hyperactivitydisorder (ADHD), hyperkinetic conduct disorder; attention deficitdisorder (ADD); conduct disorders, including but not limited todepressive conduct disorder; tic disorders including transient ticdisorder, chronic motor or vocal tic disorder, combined vocal andmultiple motor tic disorder (Gilles de la Tourette's syndrome),substance-induced tic disorders; autistic disorders; Batten disease,excessive masturbation, nail-biting, nose-picking and thumb-sucking.

Examples of disorders of psychological development that can be treatedaccording to the present invention include, but are not limited topervasive developmental disorders, including but not limited toAsperger's syndrome and Rett syndrome, autistic disorders, childhoodautism and overactive disorder associated with mental retardation andstereotyped movements, specific developmental disorder of motorfunction, specific developmental disorders of scholastic skills.

Examples of systemic atrophies primarily affecting the central nervoussystem that can be treated according to the present invention include,but are not limited to, multiple sclerosis systemic atrophies primarilyaffecting the basal ganglia including Huntington's disease, andamyotrophic lateral sclerosis.

Examples of extrapyramidal and movement disorders with malfunctionand/or degeneration of basal ganglia that can be treated according tothe present invention include, but are not limited to, Parkinson'sdisease; second Parkinsonism such as postencephalitic Parkinsonism;Parkinsonism comprised in other disorders; Niemann-Pick disease, Lewybody disease; degenerative diseases of the basal ganglia; otherextrapyramidal and movement disorders including tremor, essential tremorand drug-induced tremor, myoclonus, chorea and drug-induced chorea,drug-induced tics and tics of organic origin, drug-induced acutedystonia, drug-induced tardive dyskinesia, muscular spasms and disordersassociated with muscular spasticity or weakness including tremors;mental deficiency (including spasticity, Down syndrome and fragile Xsyndrome), L-dopa-induced dyskinesia; restless leg syndrome andStiff-man syndrome.

Further examples of movement disorders with malfunction and/ordegeneration of basal ganglia that can be treated according to thepresent invention include, but are not limited to, dystonia includingbut not limited to focal dystonia, multiple-focal or segmental dystonia,torsion dystonia, hemispheric, generalized and tardive dystonia (inducedby psychopharmacological drugs). Focal dystonia include cervicaldystonia (torticolli), blepharospasm (cramp of the eyelid), appendiculardystonia (cramp in the extremities, like the writer's cramp), ormandibular dystonia and spasmodic dysphonia (cramp of the vocal cord);neuroleptic-induced movement disorders including but not limited toneuroleptic malignant syndrome (NMS), neuroleptic-induced Parkinsonism,neuroleptic-induced early onset or acute dyskinesia, neuroleptic-inducedacute dystonia, neuroleptic-induced acute akathisia, neuroleptic-inducedtardive dyskinesia, and neuroleptic-induced tremor.

Examples of behavioral syndromes associated with physiologicaldisturbances and physical factors according to the present inventioninclude, but are not limited to, nonorganic sleep disorders, includingbut not limited to nonorganic hypersomnia, nonorganic disorder of thesleep-wake schedule (circadian rhythm sleep disorder), insomnia,parasomnia and sleep deprivation; mental and behavioral disordersassociated with the puerperium including postnatal and postpartumdepression; eating disorders, including but not limited to anorexianervosa, bulimia nervosa, binge eating disorder, hyperphagia, obesity,compulsive eating disorders and pagophagia.

Examples of disorders of adult personality and behavior that can betreated according to the present invention include, but are not limitedto, personality disorders, including but not limited to emotionallyunstable, borderline, obsessive-compulsive, anankastic, dependent andpassive-aggressive personality disorder; habit and impulse disorders(impulse-control disorder) including intermittent explosive disorder,pathological gambling, pathological fire-setting (pyromania),pathological stealing (kleptomania), trichotillomania; Munchausensyndrome.

Examples of schizophrenia and other psychotic disorders that can betreated according to the present invention include, but are not limitedto, continuous or episodic schizophrenia of different types (forinstance paranoid, hebephrenic, catatonic, undifferentiated, residual,and schizophreniform disorders); schizotypal disorders (such asborderline, latent, prepsychotic, prodromal, pseudoneuroticpseudopsychopathic schizophrenia and schizotypal personality disorder);persistent delusional disorders; acute, transient and persistentpsychotic disorders; induced delusional disorders; schizoaffectivedisorders of different type (for instance manic depressive or mixedtype); puerperal psychosis and other and unspecified nonorganicpsychosis.

Examples of mental and behavioral disorders due to psychoactivesubstance use that can be treated according to the present inventioninclude, but are not limited to, mental and behavioral disorders due touse of alcohol, opioids, cannabinoids, sedatives or hypnotics, cocaine;mental and behavioral disorders due to the use of other stimulantsincluding caffeine, mental and behavioral disorders due to drugdependence and abuse (e.g., narcotic dependence, alcoholism, amphetamineand methamphetamine dependence, opioid dependence, cocaine addiction,nicotine dependence, and drug withdrawal syndrome, and relapseprevention), use of hallucinogens, tobacco (nicotine), volatile solventsand mental and behavioral disorders due to multiple drug use and use ofother psychoactive substances including the following subtype symptoms:harmful use, dependence syndrome, withdrawal state, and withdrawal statewith delirium.

Examples of dementia that can be treated according to the presentinvention include, but are not limited to, vascular dementia, dementiadue to Creutzfeld-Jacob disease, HIV, head trauma, Parkinson's,Huntington's, Pick's disease, dementia of the Alzheimer's type.

In certain embodiments, the present invention is directed to methods forthe treatment of schizophrenia by administration of a therapeuticallyeffective amount of a compound of the present invention to a patient inneed thereof.

In certain other embodiments, the invention is further directed to amethod for the treatment of cognitive impairment associated withschizophrenia by administration of a therapeutically effective amount ofa compound of the present invention to a patient in need thereof.

In addition to the central nervous system disorders mentioned above,there is extensive literature in the art describing the effects of PDEinhibitors on various autoimmune and inflammatory cell responses, whichin addition to cAMP increase, include inhibition of superoxideproduction, degranulation, chemotaxis and tumor necrosis factor (TNF)release in eosinophils, neutrophils and monocytes. Therefore, thecompounds of the present invention may be useful for treating autoimmuneand Inflammatory diseases. (See: Schett, G. et al., Apremilast: A novelPDE4 Inhibitor in the Treatment of Autoimmune and Inflammatory Diseases,Ther. Adv. Musculoskeletal Dis. 2010; 2(5):271-278). For example, thecompounds of the present invention may be useful for treatment of oralulcers associated with Behcet's disease. The compounds of the presentinvention may also be useful for the treatment of pain associated witharthritis (See: Hess, A. et al., Blockade of TNF-α rapidly inhibits painresponses in the central nervous system, PNAS, vol. 108, no. 9,3731-3736 (2011) or for the treatment of psoriasis or psoriaticarthritis (See: Schafer, P., Apremilast mechanism of action andapplication to psoriasis and psoriatic arthritis, Biochem. Pharmacol.(2012), 15;83(12):1583-90). Accordingly, compounds of the presentinvention may also be useful for treatment of ankylosing spondylitis[see: Patan, E. et al., Efficacy and safety of apremilast, an oralphosphodiesterase 4 inhibitor, in ankylosing spondylitis, Ann. Rheum.Dis. (Sep. 14, 2102)]. Other conditions treatable by administration ofthe compounds of the present invention include, but are not limited to,acute and chronic airway diseases such as, but not limited to, asthma,chronic or acute bronchoconstriction, chronic bronchitis,bronchiectasis, small airways obstruction, emphysema, obstructive orinflammatory airways diseases, acute respiratory distress syndrome(ARDS), COPD, pneumoconiosis, seasonal allergic rhinitis or perennialallergic rhinitis or sinusitis, and acute lung injury (ALI).

In yet another embodiment, the compounds of the present invention may beuseful for treating rheumatoid arthritis, gout, and fever, edema andpain associated with inflammation, eosinophil-related disorders,dermatitis or eczema, urticaria, conjunctivitis, uveitis, psoriasis,inflammatory bowel disease, sepsis, septic shock, liver injury,pulmonary hypertension, pulmonary edema, bone loss disease, andinfection.

In yet another embodiment, the compounds of the present invention may beuseful for treating cancer. For example, the compounds of the presentinvention may be useful for treatment of brain cancer (e.g.,medulloblastoma) (See: Schmidt, A. L., BDNF and PDE4, but not GRPR,Regulate Viability of Human Medulloblastoma Cells, J. Mol. Neuroscience(2010) 40:303-310). The compounds of the present invention may also beuseful for treating melanoma (See: Marquette, A. et al., ERK and PDE4cooperate to induce RAF isoform switching in melanoma, Nature Structural& Molecular Biology, vol. 18, no. 5, 584-91, 2011). In certainembodiments, the compounds of the present invention may be useful fortreating leukemia, e.g., chronic lymphocytic leukemia, (See: Kim, D. H.et al., Type 4 Cyclic Adenosine Monophosphate Phosphodiesterase as aTherapeutic Target in Chronic Lymphocytic Leukemia, Blood Journal of TheAmerican Society of Hematology, Oct. 1, 1998, vol. 92, no. 7 2484-2494).In other embodiments, the compounds may be useful for treating brain orophthamological tumors.

In certain other embodiments, the compounds of the present invention maybe useful for treating diabetes or diseases associated with diabetes(See: Vollert, S. et al., The glucose-lowering effects of the PDE4inhibitors roflumilast and roflumilast-N-oxide in db/db mice,Diabetologia (2012) 55:2779-2788. Wouters, E. F. M. et al., Effect ofthe Phosphodiesterase 4 Inhibitor Roflumilast on Glucose Metabolism inPatients with Treatment-Naïve, Newly Diagnosed Type 2 Diabetes Mellitus,Journal of Clinical Endocrinology and Metabolism 2012, 97, 1720-1725).Other examples include, but are not limited to, diabetic maculardegeneration, diabetic neuropathy, obesity, type 2 diabetes (non-insulindependent diabetes), metabolic syndrome, glucose intolerance, urinaryincontinence (e.g., bladder overactivity), diabetic macular edema,nephropathy and related health risks, symptoms or disorders. As such,the compounds can also be used to reduce body fat or body weight of anoverweight or obese individual.

In certain other embodiments, the compounds of the present invention maybe useful in the prevention and treatment of disorders associated withenhanced endothelial activity, impaired endothelial barrier functionand/or enhanced neoangiogenesis, such as septic shock; angioedema,peripheral edema, communicating or non-communicating hydrocephalus,vascular edema, cerebral edema; reduced natriuria pathology;inflammatory diseases, including asthma, rhinitis, arthritis andrheumatoid diseases and autoimmune diseases; acute renal or liverfailure, liver dysfunction; psoriasis, Irritable Bowel Disease (IBD),Crohn's disease, and benign/malignant neoplasia.

In certain other embodiments, the compounds of the present invention maybe useful for treating diseases of the spinal cord and/or peripheralnervous system, including spinal cord injury, spinal cord edema, spinalcord tumors, vascular malformations or anomalies of the spinal cord,syringomyelia, and hydromyelia.

In certain other embodiments, the compounds described herein are furtheruseful in the prevention and treatment of disorders associated withthrombosis, embolism, or ischemic disorders including, but not limitedto, thrombosis-induced tissue infarction in coronary artery disease, incerebrovascular disease (including cerebral arteriosclerosis, cerebralamyloid angiopathy, hereditary cerebral hemorrhage, and brainhypoxia-ischemia) and/or in peripheral vascular disease; stable andunstable angina, transient ischemic attacks, stroke, atherosclerosis,myocardial infarct, cerebral infarct, reperfusion injury(brain/cardiac), traumatic brain injury, subdural, epidural orsubarachnoid hemorrhage, migraine, cluster and tension headaches,placental insufficiency, thrombosis after surgical procedures, such asbypass, angioplasty, stent placement, and heart valve replacement.

In certain other embodiments, the compounds described herein are furtheruseful for treating pain conditions and disorders. Examples of such painconditions and disorders include, but are not limited to, inflammatorypain, hyperalgesia, inflammatory hyperalgesia, migraine, cancer pain,osteoarthritis pain, post-surgical pain, non-inflammatory pain,neuropathic pain, sub-categories of neuropathic pain includingperipheral neuropathic pain syndromes, chemotherapy-induced neuropathy,complex regional pain syndrome, HIV sensory neuropathy, neuropathysecondary to tumor infiltration, painful diabetic neuropathy, phantomlimb pain, postherpetic neuralgia, postmastectomy pain, trigeminalneuralgia, central neuropathic pain syndromes, central post-stroke pain,multiple sclerosis pain, Parkinson disease pain, and spinal cord injurypain.

In certain other embodiments, the compounds described herein are furtheruseful for treating wounds (or promoting wound healing), burns,scarring, and related conditions.

In certain other embodiments, the compounds described herein are furtheruseful for treating neuronal damage disorders (including ocular damage,retinopathy including diabetic macular edema or macular degeneration ofthe eye, tinnitus, hearing impairment and loss, and brain edema).

In certain other embodiments, the compounds described herein are furtheruseful for treating transplant rejection, allograft rejection, renal andliver failure, and restless leg syndrome.

Formulations

The compounds of the invention may be administered orally. Oraladministration may involve swallowing, so that the compound enters thegastrointestinal tract, or buccal or sublingual administration may beemployed, by which the compound enters the blood stream directly fromthe mouth.

In another embodiment, the compounds of the invention may also beadministered directly into the blood stream, into muscle, or into aninternal organ. Suitable means for parenteral administration includeintravenous, intraarterial, intraperitoneal, intrathecal,intraventricular, intraurethral, intrasternal, intracranial,intramuscular and subcutaneous. Suitable devices for parenteraladministration include needle (including microneedle) injectors,needle-free injectors and infusion techniques.

In another embodiment, the compounds of the invention may also beformulated such that administration topically to the skin or mucosa(i.e., dermally or transdermally) leads to systemic absorption of thecompound. In another embodiment, the compounds of the invention can alsobe formulated such that administration intranasally or by inhalationleads to systemic absorption of the compound. In another embodiment, thecompounds of the invention may be formulated such that administrationrectally or vaginally leads to systemic absorption of the compound.

The dosage regimen for the compounds and/or compositions containing thecompounds is based on a variety of factors, including the type, age,weight, sex and medical condition of the patient; the severity of thecondition; the route of administration; and the activity of theparticular compound employed. Thus the dosage regimen may vary widely.Dosage levels of the order from about 0.01 mg to about 100 mg perkilogram of body weight per day are useful in the treatment of theabove-indicated conditions. In one embodiment, the total daily dose of acompound of the invention (administered in single or divided doses) istypically from about 0.01 to about 100 mg/kg. In another embodiment, thetotal daily dose of the compound of the invention is from about 0.1 toabout 50 mg/kg, and in another embodiment, from about 0.5 to about 30mg/kg (i.e., mg compound of the invention per kg body weight). In oneembodiment, dosing is from 0.01 to 10 mg/kg/day. In another embodiment,dosing is from 0.1 to 1.0 mg/kg/day. Dosage unit compositions maycontain such amounts or submultiples thereof to make up the daily dose.In many instances, the administration of the compound will be repeated aplurality of times in a day (typically no greater than 4 times).Multiple doses per day typically may be used to increase the total dailydose, if desired.

For oral administration, the compositions may be provided in the form oftablets containing 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0,25.0, 50.0, 75.0, 100, 125, 150, 175, 200, 250 and 500 milligrams of theactive ingredient for the symptomatic adjustment of the dosage to thepatient. A medicament typically contains from about 0.01 mg to about 500mg of the active ingredient, or in another embodiment, from about 1 mgto about 100 mg of active ingredient. Intravenously, doses may rangefrom about 0.1 to about 10 mg/kg/minute during a constant rate infusion.

Suitable subjects according to the present invention include mammaliansubjects. Mammals according to the present invention include, but arenot limited to, canine, feline, bovine, caprine, equine, ovine, porcine,rodents, lagomorphs, primates, and the like, and encompass mammals inutero. In one embodiment, humans are suitable subjects. Human subjectsmay be of either gender and at any stage of development.

In another embodiment, the invention comprises the use of one or morecompounds of the invention for the preparation of a medicament for thetreatment of the conditions recited herein.

For the treatment of the conditions referred to above, the compounds ofthe invention can be administered as compound per se. Alternatively,pharmaceutically acceptable salts are suitable for medical applicationsbecause of their greater aqueous solubility relative to the parentcompound.

In another embodiment, the present invention comprises pharmaceuticalcompositions. Such pharmaceutical compositions comprise a compound ofthe invention presented with a pharmaceutically acceptable carrier. Thecarrier can be a solid, a liquid, or both, and may be formulated withthe compound as a unit-dose composition, for example, a tablet, whichcan contain from 0.05% to 95% by weight of the active compounds. Acompound of the invention may be coupled with suitable polymers astargetable drug carriers. Other pharmacologically active substances canalso be present.

The compounds of the present invention may be administered by anysuitable route, preferably in the form of a pharmaceutical compositionadapted to such a route, and in a dose effective for the treatmentintended. The active compounds and compositions, for example, may beadministered orally, rectally, parenterally, or topically (e.g.,intranasal or ophthalmic).

Oral administration of a solid dose form may be, for example, presentedin discrete units, such as hard or soft capsules, pills, cachets,lozenges, or tablets, each containing a predetermined amount of at leastone compound of the present invention. In another embodiment, the oraladministration may be in a powder or granule form. In anotherembodiment, the oral dose form is sub-lingual, such as, for example, alozenge. In such solid dosage forms, the compounds of the presentinvention are ordinarily combined with one or more adjuvants. Suchcapsules or tablets may contain a controlled-release formulation. In thecase of capsules, tablets, and pills, the dosage forms also may comprisebuffering agents or may be prepared with enteric coatings.

In another embodiment, oral administration may be in a liquid dose form.Liquid dosage forms for oral administration include, for example,pharmaceutically acceptable emulsions, solutions, suspensions, syrups,and elixirs containing inert diluents commonly used in the art (e.g.,water). Such compositions also may comprise adjuvants, such as wetting,emulsifying, suspending, flavoring (e.g., sweetening), and/or perfumingagents.

In another embodiment, the present invention comprises a parenteral doseform. “Parenteral administration” includes, for example, subcutaneousinjections, intravenous injections, intraperitoneal injections,intramuscular injections, intrasternal injections, and infusion.Injectable preparations (i.e., sterile injectable aqueous or oleaginoussuspensions) may be formulated according to the known art using suitabledispersing, wetting, and/or suspending agents, and include depotformulations.

In another embodiment, the present invention comprises a topical doseform. “Topical administration” includes, for example, transdermaladministration, such as via transdermal patches or iontophoresisdevices, intraocular administration, or intranasal or inhalationadministration. Compositions for topical administration also include,for example, topical gels, sprays, ointments, and creams. A topicalformulation may include a compound that enhances absorption orpenetration of the active ingredient through the skin or other affectedareas. When the compounds of this invention are administered by atransdermal device, administration will be accomplished using a patcheither of the reservoir and porous membrane type or of a solid matrixvariety. Typical formulations for this purpose include gels, hydrogels,lotions, solutions, creams, ointments, dusting powders, dressings,foams, films, skin patches, wafers, implants, sponges, fibers, bandagesand microemulsions. Liposomes may also be used. Typical carriers includealcohol, water, mineral oil, liquid petrolatum, white petrolatum,glycerin, polyethylene glycol and propylene glycol. Penetrationenhancers may be incorporated—see, for example, Finnin and Morgan, J.Pharm. Sci., 88 (10), 955-958 (1999).

Formulations suitable for topical administration to the eye include, forexample, eye drops wherein the compound of this invention is dissolvedor suspended in a suitable carrier. A typical formulation suitable forocular or aural administration may be in the form of drops of amicronized suspension or solution in isotonic, pH-adjusted, sterilesaline. Other formulations suitable for ocular and aural administrationinclude ointments, biodegradable (e.g., absorbable gel sponges,collagen) and non-biodegradable (e.g., silicone) implants, wafers,lenses and particulate or vesicular systems, such as niosomes orliposomes. A polymer such as crossed-linked polyacrylic acid, polyvinylalcohol, hyaluronic acid, a cellulosic polymer, for example,hydroxypropylmethyl cellulose, hydroxyethyl cellulose, or methylcellulose, or a heteropolysaccharide polymer, for example, gelan gum,may be incorporated together with a preservative, such as benzalkoniumchloride. Such formulations may also be delivered by iontophoresis.

For intranasal administration or administration by inhalation, theactive compounds of the invention are conveniently delivered in the formof a solution or suspension from a pump spray container that is squeezedor pumped by the patient or as an aerosol spray presentation from apressurized container or a nebulizer, with the use of a suitablepropellant. Formulations suitable for intranasal administration aretypically administered in the form of a dry powder (either alone; as amixture, for example, in a dry blend with lactose; or as a mixedcomponent particle, for example, mixed with phospholipids, such asphosphatidylcholine) from a dry powder inhaler or as an aerosol sprayfrom a pressurized container, pump, spray, atomizer (preferably anatomizer using electrohydrodynamics to produce a fine mist), ornebulizer, with or without the use of a suitable propellant, such as1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane. Forintranasal use, the powder may comprise a bioadhesive agent, forexample, chitosan or cyclodextrin.

In another embodiment, the present invention comprises a rectal doseform. Such rectal dose form may be in the form of, for example, asuppository. Cocoa butter is a traditional suppository base, but variousalternatives may be used as appropriate.

Other carrier materials and modes of administration known in thepharmaceutical art may also be used. Pharmaceutical compositions of theinvention may be prepared by any of the well-known techniques ofpharmacy, such as effective formulation and administration procedures.The above considerations in regard to effective formulations andadministration procedures are well known in the art and are described instandard textbooks. Formulation of drugs is discussed in, for example,Hoover, John E., Remington's Pharmaceutical Sciences, Mack PublishingCo., Easton, Pa., 1975; Liberman et al., Eds., Pharmaceutical DosageForms, Marcel Decker, New York, N.Y., 1980; and Kibbe et al., Eds.,Handbook of Pharmaceutical Excipients (3^(rd) Ed.), AmericanPharmaceutical Association, Washington, 1999.

The compounds of the present invention can be used, alone or incombination with other therapeutic agents, in the treatment of variousconditions or disease states. The compound(s) of the present inventionand other therapeutic agent(s) may be administered simultaneously(either in the same dosage form or in separate dosage forms) orsequentially. An exemplary therapeutic agent may be, for example, ametabotropic glutamate receptor agonist.

The administration of two or more compounds “in combination” means thatthe two compounds are administered closely enough in time that thepresence of one alters the biological effects of the other. The two ormore compounds may be administered simultaneously, concurrently orsequentially. Additionally, simultaneous administration may be carriedout by mixing the compounds prior to administration or by administeringthe compounds at the same point in time but at different anatomic sitesor using different routes of administration.

The phrases “concurrent administration,” “co-administration,”“simultaneous administration,” and “administered simultaneously” meanthat the compounds are administered in combination.

The present invention includes the use of a combination of a PDE4inhibitor compound of the present invention and one or more additionalpharmaceutically active agent(s). If a combination of active agents isadministered, then they may be administered sequentially orsimultaneously, in separate dosage forms or combined in a single dosageform. Accordingly, the present invention also includes pharmaceuticalcompositions comprising an amount of: (a) a first agent comprising acompound of the present invention or a pharmaceutically acceptable saltof the compound; (b) a second pharmaceutically active agent; and (c) apharmaceutically acceptable carrier, vehicle or diluent.

Various pharmaceutically active agents may be selected for use inconjunction with the compounds of the present invention, depending onthe disease, disorder, or condition to be treated. Pharmaceuticallyactive agents that may be used in combination with the compositions ofthe present invention include, without limitation:

(i) acetylcholinesterase inhibitors, such as donepezil hydrochloride(ARICEPT, MEMAC), physostigmine salicylate (ANTILIRIUM), physostigminesulfate (ESERINE), metrifonate, neostigmine, ganstigmine, pyridostigmine(MESTINON), ambenonium (MYTELASE), demarcarium, Debio 9902 (also knownas ZT-1; Debiopharm), rivastigmine (EXELON), ladostigil, NP-0361,galantamine hydrobromide (RAZADYNE, RIMINYL, NIVALIN), tacrine (COGNEX),tolserine, velnacrine maleate, memoquin, huperzine A (HUP-A;NeuroHitech), phenserine, edrophonium (ENLON, TENSILON), and INM-176;

(ii) amyloid-ß (or fragments thereof), such as Aß₁₋₁₅ conjugated to panHLA DR-binding epitope (PADRE), ACC-001 (Elan/Wyeth), ACI-01, ACI-24,AN-1792, Affitope AD-01, CAD106, and V-950;

(iii) antibodies to amyloid-ß (or fragments thereof), such as ponezumab,solanezumab, bapineuzumab (also known as AAB-001), AAB-002 (Wyeth/Elan),ACI-01-Ab7, BAN-2401, intravenous Ig (GAMMAGARD), LY2062430 (humanizedm266; Lilly), R1450 (Roche), ACU-5A5, huC091, and those disclosed inInternational Patent Publication Nos WO04/032868, WO05/025616,WO06/036291, WO06/069081, WO06/118959, in US Patent Publication NosUS2003/0073655, US2004/0192898, US2005/0048049, US2005/0019328, inEuropean Patent Publication Nos EP0994728 and 1257584, and in U.S. Pat.No 5,750,349;

(iv) amyloid-lowering or -inhibiting agents (including those that reduceamyloid production, accumulation and fibrillization) such as dimebon,davunetide, eprodisate, leuprolide, SK-PC-B70M, celecoxib, lovastatin,anapsos, oxiracetam, pramiracetam, varenicline, nicergoline,colostrinin, bisnorcymserine (also known as BNC), NIC5-15 (Humanetics),E-2012 (Eisai), pioglitazone, clioquinol (also known as PBT1), PBT2(Prana Biotechnology), flurbiprofen (ANSAID, FROBEN) and itsR-enantiomer tarenflurbil (FLURIZAN), nitroflurbiprofen, fenoprofen(FENOPRON, NALFON), ibuprofen (ADVIL, MOTRIN, NUROFEN), ibuprofenlysinate, meclofenamic acid, meclofenamate sodium (MECLOMEN),indomethacin (INDOCIN), diclofenac sodium (VOLTAREN), diclofenacpotassium, sulindac (CLINORIL), sulindac sulfide, diflunisal (DOLOBID),naproxen (NAPROSYN), naproxen sodium (ANAPROX, ALEVE), ARC031 (ArcherPharmaceuticals), CAD-106 (Cytos), LY450139 (Lilly), insulin-degradingenzyme (also known as insulysin), the gingko biloba extract EGb-761(ROKAN, TEBONIN), tramiprosate (CEREBRIL, ALZHEMED), eprodisate(FIBRILLEX, KIACTA), compound W [3,5-bis(4-nitrophenoxy)benzoic acid],NGX-96992, neprilysin (also known as neutral endopeptidase (NEP)),scyllo-inositol (also known as scyllitol), atorvastatin (LIPITOR),simvastatin (ZOCOR), KLVFF-(EEX)3, SKF-74652, ibutamoren mesylate, BACEinhibitors such as ASP-1702, SCH-745966, JNJ-715754, AMG-0683,AZ-12304146, BMS-782450, GSK-188909, NB-533, E2609 and TTP-854; gammasecretase modulators such as ELND-007; and RAGE (receptor for advancedglycation end-products) inhibitors, such as TTP488 (Transtech) andTTP4000 (Transtech), and those disclosed in U.S. Pat. No. 7,285,293,including PTI-777;

(v) alpha-adrenergic receptor agonists, such as guanfacine (INTUNIV,TENEX), clonidine (CATAPRES), metaraminol (ARAMINE), methyldopa(ALDOMET, DOPAMET, NOVOMEDOPA), tizanidine (ZANAFLEX), phenylephrine(also known as neosynephrine), methoxamine, cirazoline, guanfacine(INTUNIV), lofexidine, xylazine, modafinil (PROVIGIL), adrafinil, andarmodafinil (NUVIGIL);

(vi) beta-adrenergic receptor blocking agents (beta blockers), such ascarteolol, esmolol (BREVIBLOC), labetalol (NORMODYNE, TRANDATE),oxprenolol (LARACOR, TRASACOR), pindolol (VISKEN), propanolol (INDERAL),sotalol (BETAPACE, SOTALEX, SOTACOR), timolol (BLOCADREN, TIMOPTIC),acebutolol (SECTRAL, PRENT), nadolol (CORGARD), metoprolol tartrate(LOPRESSOR), metoprolol succinate (TOPROL-XL), atenolol (TENORMIN),butoxamine, and SR 59230A (Sanofi);

(vii) anticholinergics, such as amitriptyline (ELAVIL, ENDEP),butriptyline, benztropine mesylate (COGENTIN), trihexyphenidyl (ARTANE),diphenhydramine (BENADRYL), orphenadrine (NORFLEX), hyoscyamine,atropine (ATROPEN), scopolamine (TRANSDERM-SCOP), scopolaminemethylbromide (PARMINE), dicycloverine (BENTYL, BYCLOMINE, DIBENT,DILOMINE), tolterodine (DETROL), oxybutynin (DITROPAN, LYRINEL XL,OXYTROL), penthienate bromide, propantheline (PRO-BANTHINE), cyclizine,imipramine hydrochloride (TOFRANIL), imipramine maleate (SURMONTIL),lofepramine, desipramine (NORPRAMIN), doxepin (SINEQUAN, ZONALON),trimipramine (SURMONTIL), and glycopyrrolate (ROBINUL);

(viii) anticonvulsants, such as carbamazepine (TEGRETOL, CARBATROL),oxcarbazepine (TRILEPTAL), phenytoin sodium (PHENYTEK), fosphenytoin(CEREBYX, PRODILANTIN), divalproex sodium (DEPAKOTE), gabapentin(NEURONTIN), pregabalin (LYRICA), topirimate (TOPAMAX), valproic acid(DEPAKENE), valproate sodium (DEPACON), 1-benzyl-5-bromouracil,progabide, beclamide, zonisamide (TRERIEF, EXCEGRAN), CP-465022,retigabine, talampanel, and primidone (MYSOLINE);

(ix) antipsychotics, such as lurasidone (LATUDA, also known as SM-13496;Dainippon Sumitomo), aripiprazole (ABILIFY), chlorpromazine (THORAZINE),haloperidol (HALDOL), iloperidone (FANAPTA), flupentixol decanoate(DEPIXOL, FLUANXOL), reserpine (SERPLAN), pimozide (ORAP), fluphenazinedecanoate, fluphenazine hydrochloride, prochlorperazine (COMPRO),asenapine (SAPHRIS), loxapine (LOXITANE), molindone (MOBAN),perphenazine, thioridazine, thiothixine, trifluoperazine (STELAZINE),ramelteon, clozapine (CLOZARIL), norclozapine (ACP-104), risperidone(RISPERDAL), paliperidone (INVEGA), melperone, olanzapine (ZYPREXA),quetiapine (SEROQUEL), talnetant, amisulpride, ziprasidone (GEODON)blonanserin (LONASEN), and ACP-103 (Acadia Pharmaceuticals);

(x) calcium channel blockers such as lomerizine, ziconotide, nilvadipine(ESCOR, NIVADIL), diperdipine, amlodipine (NORVASC, ISTIN, AMLODIN),felodipine (PLENDIL), nicardipine (CARDENE), nifedipine (ADALAT,PROCARDIA), MEM 1003 and its parent compound nimodipine (NIMOTOP),nisoldipine (SULAR), nitrendipine, lacidipine (LACIPIL, MOTENS),lercanidipine (ZANIDIP), lifarizine, diltiazem (CARDIZEM), verapamil(CALAN, VERELAN), AR-R 18565 (AstraZeneca), and enecadin;

(xi) catechol O-methyltransferase (COMT) inhibitors, such as nitecapone,tolcapone (TASMAR), entacapone (COMTAN), and tropolone;

(xii) central nervous system stimulants, such as atomoxetine,reboxetine, yohimbine, caffeine, phenmetrazine, phendimetrazine,pemoline, fencamfamine (GLUCOENERGAN, REACTIVAN), fenethylline(CAPTAGON), pipradol (MERETRAN), deanol (also known asdimethylaminoethanol), methylphenidate (DAYTRANA), methylphenidatehydrochloride (RITALIN), dexmethylphenidate (FOCALIN), amphetamine(alone or in combination with other CNS stimulants, e.g., ADDERALL(amphetamine aspartate, amphetamine sulfate, dextroamphetaminesaccharate, and dextroamphetamine sulfate)), dextroamphetamine sulfate(DEXEDRINE, DEXTROSTAT), methamphetamine (DESOXYN), lisdexamfetamine(VYVANSE), and benzphetam ine (DIDREX);

(xiii) corticosteroids, such as prednisone (STERAPRED, DELTASONE),prednisolone (PRELONE), predisolone acetate (OMNIPRED, PRED MILD, PREDFORTE), prednisolone sodium phosphate (ORAPRED ODT), methylprednisolone(MEDROL); methylprednisolone acetate (DEPO-MEDROL), andmethylprednisolone sodium succinate (A-METHAPRED, SOLU-MEDROL);

(xiv) dopamine receptor agonists, such as apomorphine (APOKYN),bromocriptine (PARLODEL), cabergoline (DOSTINEX), dihydrexidine,dihydroergocryptine, fenoldopam (CORLOPAM), lisuride (DOPERGIN),terguride spergolide (PERMAX), piribedil (TRIVASTAL, TRASTAL),pramipexole (MIRAPEX), quinpirole, ropinirole (REQUIP), rotigotine(NEUPRO), SKF-82958 (GlaxoSmithKline), cariprazine, pardoprunox andsarizotan;

(xv) dopamine receptor antagonists, such as chlorpromazine,fluphenazine, haloperidol, loxapine, risperidone, thioridazine,thiothixene, trifluoperazine, tetrabenazine (NITOMAN, XENAZINE),7-hydroxyamoxapine, droperidol (INAPSINE, DRIDOL, DROPLETAN),domperidone (MOTILIUM), L-741742, L-745870, raclopride, SB-277011A,SCH-23390, ecopipam, SKF-83566, and metoclopramide (REGLAN);

(xvi) dopamine reuptake inhibitors such as bupropion, safinamide,nomifensine maleate (MERITAL), vanoxerine (also known as GBR-12909) andits decanoate ester DBL-583, and amineptine;

(xvii) gamma-amino-butyric acid (GABA) receptor agonists, such asbaclofen (LIORESAL, KEMSTRO), siclofen, pentobarbital (NEMBUTAL),progabide (GABRENE), and clomethiazole;

(xviii) histamine 3 (H3) antagonists such as ciproxifan, tiprolisant,S-38093, irdabisant, pitolisant, GSK-239512, GSK-207040, JNJ-5207852,JNJ-17216498, HPP-404, SAR-110894,trans-N-ethyl-3-fluoro-3-[3-fluoro-4-(pyrrolidin-1-ylmethyl)phenyl]-cyclobutanecarboxamide(PF-3654746 and those disclosed in US Patent Publication NosUS2005-0043354, US2005-0267095, US2005-0256135, US2008-0096955,US2007-1079175, and US2008-0176925; International Patent Publication NosWO2006/136924, WO2007/063385, WO2007/069053, WO2007/088450,WO2007/099423, WO2007/105053, WO2007/138431, and WO2007/088462; and U.S.Pat. No. 7,115,600);

(xix) immunomodulators such as glatiramer acetate (also known ascopolymer-1; COPAXONE), MBP-8298 (synthetic myelin basic proteinpeptide), dimethyl fumarate, fingolimod (also known as FTY720),roquinimex (LINOMIDE), laquinimod (also known as ABR-215062 andSAIK-MS), ABT-874 (human anti-IL-12 antibody; Abbott), rituximab(RITUXAN), alemtuzumab (CAMPATH), daclizumab (ZENAPAX), and natalizumab(TYSABRI);

(xx) immunosuppressants such as methotrexate (TREXALL, RHEUMATREX),mitoxantrone (NOVANTRONE), mycophenolate mofetil (CELLCEPT),mycophenolate sodium (MYFORTIC), azathioprine (AZASAN, IMURAN),mercaptopurine (PURI-NETHOL), cyclophosphamide (NEOSAR, CYTOXAN),chlorambucil (LEUKERAN), cladribine (LEUSTATIN, MYLINAX),alpha-fetoprotein, etanercept (ENBREL), and4-(benzyloxy)-5-[(5-undecyk2H-pyrrol-2-ylidene)methyl]-1H,1′H-2,2′-bipyrrole(also known as PNU-156804);

(xxi) interferons, including interferon beta-1a (AVONEX, REBIF) andinterferon beta-1b (BETASERON, BETAFERON);

(xxii) levodopa (or its methyl or ethyl ester), alone or in combinationwith a DOPA decarboxylase inhibitor (e.g., carbidopa (SINEMET, CARBILEV,PARCOPA), benserazide (MADOPAR), u-methyldopa, monofluromethyldopa,difluoromethyldopa, brocresine, or m-hydroxybenzylhydrazine);

(xxiii) N-methyl-D-aspartate (NMDA) receptor antagonists, such asmemantine (NAMENDA, AXURA, EBIXA), amantadine (SYMMETREL), acamprosate(CAMPRAL), besonprodil, ketamine (KETALAR), delucemine, dexanabinol,dexefaroxan, dextromethorphan, dextrorphan, traxoprodil, CP-283097,himantane, idantadol, ipenoxazone, L-701252 (Merck), lancicemine,levorphanol (DROMORAN), LY-233536 and LY-235959 (both Lilly), methadone,(DOLOPHINE), neramexane, perzinfotel, phencyclidine, tianeptine(STABLON), dizocilpine (also known as MK-801), EAB-318 (Wyeth),ibogaine, voacangine, tiletamine, riluzole (RILUTEK), aptiganel(CERESOTAT), gavestinel, and remacimide;

(xxiv) monoamine oxidase (MAO) inhibitors, such as selegiline (EMSAM),selegiline hydrochloride (I-deprenyl, ELDEPRYL, ZELAPAR),dimethylselegilene, brofaromine, phenelzine (NARDIL), tranylcypromine(PARNATE), moclobemide (AURORIX, MANERIX), befloxatone, safinamide,isocarboxazid (MARPLAN), nialamide (NIAMID), rasagiline (AZILECT),iproniazide (MARSILID, IPROZID, IPRONID), CHF-3381 (ChiesiFarmaceutici), iproclozide, toloxatone (HUMORYL, PERENUM), bifemelane,desoxypeganine, harmine (also known as telepathine or banasterine),harmaline, linezolid (ZYVOX, ZYVOXID), and pargyline (EUDATIN,SUPIRDYL);

(xxv) muscarinic receptor (particularly M1 subtype) agonists, such ascevimeline, levetiracetam, bethanechol chloride (DUVOID, URECHOLINE),itameline, pilocarpine (SALAGEN), NGX267, arecoline, L-687306 (Merck),L-689660 (Merck), furtrethonium iodide (FURAMON, FURANOL), furtrethoniumbenzensulfonate, furtrethonium p-toluenesulfonate, McN-A-343,oxotremorine, sabcomeline, AC-90222 (Acadia Pharmaceuticals), andcarbachol (CARBASTAT, MIOSTAT, CARBOPTIC);

(xxvi) neuroprotective drugs such as bosutinib, condoliase, airmoclomol,lamotrigine, perampenel, aniracetam, minaprime, riluzole,N-hydroxy-1,2,4,9-tetrahydro-3H-carbazol-3-imine, desmoteplase,anatibant, astaxanthin, neuropeptide NAP (e.g., AL-108 and AL-208; bothAllon Therapeutics), neurostrol, perampenel, ispronicline,bis(4-β-D-glucopyranosyloxybenzyl)-2-β-D-glucopyranosyl-2-isobutyltartrate(also known as dactylorhin B or DHB), formobactin, xaliproden (XAPRILA),lactacystin, dimeboline hydrochloride (DIMEBON), disufenton (CEROVIVE),arundic acid (ONO-2506, PROGLIA, CEREACT), citicoline (also known ascytidine 5′-diphosphocholine), edaravone (RADICUT), AEOL-10113 andAEOL-10150 (both Aeolus Pharmaceuticals), AGY-94806 (also known asSA-450 and Msc-1), granulocyte-colony stimulating factor (also known asAX-200), BAY-38-7271 (also known as KN-387271; Bayer AG), ancrod(VIPRINEX, ARWIN), DP-b99 (D-Pharm Ltd), HF-0220(17-ß-hydroxyepiandrosterone; Newron Pharmaceuticals), HF-0420 (alsoknown as oligotropin), pyridoxal 5′-phosphate (also known as MC-1),microplasmin, S-18986, piclozotan, NP031112, tacrolimus,L-seryl-L-methionyl-L-alanyl-L-lysyl-L-glutamyl-glycyl-L-valine,AC-184897 (Acadia Pharmaceuticals), ADNF-14 (National Institutes ofHealth), stilbazulenyl nitrone, SUN-N8075 (Daiichi Suntory BiomedicalResearch), and zonampanel;

(xxvii) nicotinic receptor agonists, such as epibatidine, bupropion,CP-601927, varenicline, ABT-089 (Abbott), ABT-594, AZD-0328(AstraZeneca), EVP-6124, R3487 (also known as MEM3454; Roche/MemoryPharmaceuticals), R4996 (also known as MEM63908; Roche/MemoryPharmaceuticals), TC-4959 and TC-5619 (both Targacept), and RJR-2403;

(xxviii) norepinephrine (noradrenaline) reuptake inhibitors, such asatomoxetine (STRATTERA), doxepin (APONAL, ADAPIN, SINEQUAN),nortriptyline (AVENTYL, PAMELOR, NORTRILEN), amoxapine (ASENDIN,DEMOLOX, MOXIDIL), reboxetine (EDRONAX, VESTRA), viloxazine (VIVALAN),maprotiline (DEPRILEPT, LUDIOMIL, PSYMION), bupropion (WELLBUTRIN), andradaxafine;

(xxix) phosphodiesterase (PDE) inhibitors, including but not limited to,(a) PDE1 inhibitors (e.g., vinpocetine (CAVINTON, CERACTIN, INTELECTOL)and those disclosed in U.S. Pat. No. 6,235,742, (b) PDE2 inhibitors(e.g., erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA), BAY 60-7550, andthose described in U.S. Pat. No. 6,174,884), (c) PDE3 inhibitors (e.g.,anagrelide, cilostazol, milrinone, olprinone, parogrelil, andpimobendan), (d) PDE4 inhibitors (e.g., apremilast,ibudilastroflumilast, rolipram, Ro 20-1724, ibudilast (KETAS),piclamilast (also known as RP73401), CDP840, cilomilast (ARIFLO),roflumilast, tofimilast, oglemilast (also known as GRC 3886), tetomilast(also known as OPC-6535), lirimifast, theophylline (UNIPHYL, THEOLAIR),arofylline (also known as LAS-31025), doxofylline, RPR-122818, ormesembrine), and (e) PDE5 inhibitors (e.g., sildenafil (VIAGRA,REVATIO), tadalafil (CIALIS), vardenafil (LEVITRA, VIVANZA), udenafil,avanafil, dipyridamole (PERSANTINE), E-4010, E-4021, E-8010, zaprinast,iodenafil, mirodenafil, DA-8159, and those disclosed in InternationalPatent Applications WO2002/020521, WO2005/049616, WO2006/120552,WO2006/126081, WO2006/126082, WO2006/126083, and WO2007/122466), (f)PDE7 inhibitors; (g) PDE8 inhibitors; (h) PDE9 inhibitors (e.g., BAY73-6691 (Bayer AG) and those disclosed in US Patent Publication NosUS2003/0195205, US2004/0220186, US2006/0111372, US2006/0106035, and U.S.Ser. No. 12/118,062 (filed May 9, 2008)), (i) PDE10 inhibitors such as2-({4-[1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl]phenoxy}methyl)quinolin-3(4H)-oneand SCH-1518291; and (j) PDE11 inhibitors;

(xxx) quinolines, such as quinine (including its hydrochloride,dihydrochloride, sulfate, bisulfate and gluconate salts), chloroquine,sontoquine, hydroxychloroquine (PLAQUENIL), mefloquine (LARIAM), andamodiaquine (CAMOQUIN, FLAVOQUINE);

(xxxi) β-secretase inhibitors, such as ASP-1702, SCH-745966, JNJ-715754,AMG-0683, AZ-12304146, BMS-782450, GSK-188909, NB-533, LY-2886721,E-2609, HPP-854, (+)-phenserine tartrate (POSIPHEN), LSN-2434074 (alsoknown as LY-2434074), KMI-574, SCH-745966, Ac-rER(N²-acetyl-D-arginyl-L-arginine), loxistatin (also known as E64d), andCA074Me;

(xxxii) γ-secretase inhibitors and modulators, such as BMS-708163(Avagacest), WO20060430064 (Merck), DSP8658 (Dainippon), ITI-009,L-685458 (Merck), ELAN-G, ELAN-Z,4-chloro-N-[(2S)-3-ethyl-1-hydroxypentan-2-yl]benzenesulfonamide;

(xxxiii) serotonin (5-hydroxytryptamine) 1A (5-HT_(1A)) receptorantagonists, such as spiperone, levo-pindolol, BMY 7378, NAD-299,S-(−)-UH-301, NAN 190, lecozotan;

(xxxiv) serotonin (5-hydroxytryptamine) 2C (5-HT_(2c)) receptoragonists, such as vabicaserin and zicronapine;

(xxxv) serotonin (5-hydroxytryptamine) 4 (5-HT₄) receptor agonists, suchas PRX-03140 (Epix);

(xxxvi) serotonin (5-hydroxytryptamine) 6 (5-HT₆) receptor antagonists,such as A-964324, AVI-101, AVN-211, mianserin (TORVOL, BOLVIDON,NORVAL), methiothepin (also known as metitepine), ritanserin, ALX-1161,ALX-1175, MS-245, LY-483518 (also known as SGS518; Lilly), MS-245, Ro04-6790, Ro 43-68544, Ro 63-0563, Ro 65-7199, Ro 65-7674, SB-399885,SB-214111, SB-258510, SB-271046, SB-357134, SB-699929, SB-271046,SB-742457 (GlaxoSmithKline), Lu AE58054 (Lundbeck A/S), and PRX-07034(Epix);

(xxxvii) serotonin (5-HT) reuptake inhibitors such as alaproclate,citalopram (CELEXA, CIPRAMIL), escitalopram (LEXAPRO, CIPRALEX),clomipramine (ANAFRANIL), duloxetine (CYMBALTA), femoxetine (MALEXIL),fenfluramine (PONDIMIN), norfenfluramine, fluoxetine (PROZAC),fluvoxamine (LUVOX), indalpine, milnacipran (IXEL), paroxetine (PAXIL,SEROXAT), sertraline (ZOLOFT, LUSTRAL), trazodone (DESYREL, MOLIPAXIN),venlafaxine (EFFEXOR), zimelidine (NORMUD, ZELMID), bicifadine,desvenlafaxine (PRISTIQ), brasofensine, vilazodone, cariprazine,neuralstem and tesofensine;

(xxxviii) trophic factors, such as nerve growth factor (NGF), basicfibroblast growth factor (bFGF; ERSOFERMIN), neurotrophin-3 (NT-3),cardiotrophin-1, brain-derived neurotrophic factor (BDNF), neublastin,meteorin, and glial-derived neurotrophic factor (GDNF), and agents thatstimulate production of trophic factors, such as propentofylline,idebenone, PYM50028 (COGANE; Phytopharm), and AIT-082 (NEOTROFIN);

(xxxix) Glycine transporter-1 inhibitors such as paliflutine, ORG-25935,JNJ-17305600, and ORG-26041;

(xl) AMPA-type glutamate receptor modulators such as perampanel,mibampator, selurampanel, GSK-729327,N-{(3S,4S)-4-[4-(5-cyanothiophen-2-yl)phenoxy]tetrahydro-furan-3-yl}propane-2-sulfonamide,and the like.

(xli) Janus kinase inhibitors (JAK) such as, but not limited to,tofacitinib, ruxolitinib, baricitinib, CYT387, GLPG0634, lestaurtinib,pacritinib, and TG101348.

(xlii) Interleukin-1 receptor-associated kinase 4 inhibitors (IRAK4)such as, but not limited to, PF-06650833.

The present invention further comprises kits that are suitable for usein performing the methods of treatment described above. In oneembodiment, the kit contains a first dosage form comprising one or moreof the compounds of the present invention and a container for thedosage, in quantities sufficient to carry out the methods of the presentinvention.

In another embodiment, the kit of the present invention comprises one ormore compounds of the invention.

The compounds of the invention, or their pharmaceutically acceptablesalts, may be prepared by a variety of methods that are analogouslyknown in the art. The reaction Scheme described below, together withsynthetic methods known in the art of organic chemistry, ormodifications and derivatizations that are familiar to those of ordinaryskill in the art, illustrate a method for preparing the compounds.Others, including modifications thereof, will be readily apparent to oneskilled in the art.

The starting materials used herein are commercially available or may beprepared by routine methods known in the art (such as those methodsdisclosed in standard reference books such as the COMPENDIUM OF ORGANICSYNTHETIC METHODS, Vol. I-XII (published by Wiley-Interscience)).Preferred methods include, but are not limited to, those describedbelow.

During any of the following synthetic sequences, it may be necessaryand/or desirable to protect sensitive or reactive groups on any of themolecules concerned. This can be achieved by means of conventionalprotecting groups, such as those described in T. W. Greene, ProtectiveGroups in Organic Chemistry, John Wiley & Sons, 1981; T. W. Greene andP. G. M. Wuts, Protective Groups in Organic Chemistry, John Wiley &Sons, 1991; and T. W. Greene and P. G. M. Wuts, Protective Groups inOrganic Chemistry, John Wiley & Sons, 1999; and T. W. Greene and P. G.M. Wuts, Protective Groups in Organic Chemistry, John Wiley & Sons,2006, which are hereby incorporated by reference.

Compounds of the present invention, or the pharmaceutically acceptablesalts of said compounds or tautomers and radioisotopes, can be preparedaccording to the reaction Schemes discussed herein below. Unlessotherwise indicated, the substituents in the Schemes are defined asabove. Isolation and purification of the products is accomplished bystandard procedures, which are known to a chemist of ordinary skill.

One skilled in the art will recognize that in some cases, the compoundsin Scheme 1 will be generated as a mixture of diastereomers and/orenantiomers; these may be separated at various stages of the syntheticScheme using conventional techniques or a combination of suchtechniques, such as, but not limited to, crystallization, normal-phasechromatography, reversed phase chromatography and chiral chromatography,to afford the single enantiomers of the invention.

It will be understood by one skilled in the art that the varioussymbols, superscripts and subscripts used in the Scheme, methods andexamples are used for convenience of representation and/or to reflectthe order in which they are introduced in the Scheme, and are notintended to necessarily correspond to the symbols, superscripts orsubscripts in the appended claims. The Scheme is representative ofmethods useful in synthesizing the compounds of the present invention.They are not to constrain the scope of the invention in any way.

Scheme 1 below illustrates one synthetic pathway for the preparation ofcompounds of Formula I, as depicted above, wherein the startinghydroxypyrazole AA, whose synthesis has been described previously (WO2003/035644 and Chemical & Pharmaceutical Bulletin 1983, 31(4),1228-1234), is alkylated with the appropriately substituted three-carbonchain BB with leaving groups (LG) that facilitate an S_(N)2 reactionsuch as chlorine, bromine, and iodine and methanesulphonate,benzenesulphonate, and p-chlorobenzenesulphonate. This bis-alkylation isaccomplished by combining AA with BB in an appropriate solvent in thepresence of a base to give the pyrazolo-oxazine compounds CC, whosesynthesis wherein R⁴═H has previously been described (Journal ofMedicinal Chemistry 2006, 49(15), 4623; WO 2003/093279, US 2004/0132708,and WO 2006/130588). During the bis-alkylation step, the (R⁴)_(a)substitutent of BB should be represented by the same moiety as isdesired in the final product, Formula I, or a protected variationthereof.

In the next step, the pyrazolo-oxazine compound CC is halogenated bytreatment with electrophilic halogenating reagents such asN-bromosuccinimide (NBS), N-iodosuccinimide (NIS), bromine, or iodine inan appropriately inert solvent to give the halo-pyrazolo-oxazinecompound DD (see examples WO 2011092187; Chemische Berichte 1976,109(1), 261-7; Journal of Medicinal Chemistry 2012, 55(17), 7636-7649).

In a further step, the transformation of the halo-pyrazolo-oxazine DD tocompounds of Formula I occurs through one of two different reactionsequences.

One reaction sequence starts with a Suzuki-Miyaura-type couplingreaction (Chemical Society Reviews 2014, 43, 412-443; Accounts ofChemical Research 2013, 46, 2626-2634) wherein DD is treated with anappropriate boronate (e.g., alkyl, aryl, or heteroaryl, etc . . . ) inthe presence of base, a transition metal catalyst [potentiallybis[di-tert-butyl(4-dimethylaminophenyl)phosphine]dichloropalladium(II)or 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)], and ametal-chelating ligand (generally phosphine-based), in an appropriatesolvent to install the appropriate R¹ moiety to provide an R¹substituted ester EE. During this step, the R¹ substituent of the alkyl,aryl, or heteroaryl boronate should be represented by the same moiety asis desired in the final product, Formula I, or a protected variationthereof.

The ester EE is then converted to the desired Formula I by treatment ofthe ester EE with the appropriate amine in the presence of heat and aLewis acid, such as magnesium methoxide or calcium chloride.Alternatively, transformation of EE to Formula I is carried out in atwo-step process in which the ester is hydrolyzed to an acid bytreatment with basic or acidic water in a suitable co-solvent. Theresulting acid is then converted to Formula I by treatment with theappropriate amine in the presence of an amide coupling/dehydratingreagent such as 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane2,4,6-trioxide (T3P),O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU), 1,3-dicyclohexylcarbodiimide (DCC), etc., attemperatures ranging from −20° C. to 100° C. During either of thesesteps, the R² and R³ substituents of the amine should be independentlyrepresented by the same moiety as is desired in the final product,Formula I, or a protected variation thereof.

As previously mentioned, the transformation of the halo-pyrazolo-oxazineDD to compounds of Formula I occurs through one of two differentreaction sequences. The second sequence for the conversion ofhalo-pyrazolo-oxazine (DD) into compounds of Formula I is conversion ofthe ester to the desired amide by treatment with the appropriate amine,as described previously, to provide intermediate FF. Alternatively,transformation of DD to intermediate FF may be carried out in a two-stepprocess in which the ester is hydrolyzed to an acid and the resultingacid is then converted to Formula I by treatment with the appropriateamine in the presence of an amide coupling/dehydrating reagent aspreviously described. During either of these steps, the R² and R³substituents of the amine should be independently represented by thesame moiety as is desired in the final product, Formula I, or aprotected variation thereof.

Finally, amide FF is then converted to the desired Formula I through aSuzuki-Miyaura-type coupling with the appropriate boronate (e.g., alkyl,aryl, or heteroaryl, etc . . . ) [(RO)₂B—R¹]. During this step, the R¹substituent of the alkyl, aryl, or heteroaryl boronate should berepresented by the same moiety as is desired in the final product,Formula I, or a protected variation thereof.

Experimental Procedures

The following illustrate the synthesis of various compounds of thepresent invention. Additional compounds within the scope of thisinvention may be prepared using the methods illustrated in theseExamples, either alone or in combination with techniques generally knownin the art.

Experiments were generally carried out under inert atmosphere (nitrogenor argon), particularly in cases where oxygen- or moisture-sensitivereagents or intermediates were employed. Commercial solvents andreagents were generally used without further purification. Anhydroussolvents were employed where appropriate, generally AcroSeal® productsfrom Acros Organics or DriSolv® products from EMD Chemicals. In othercases, commercial solvents were passed through columns packed with 4 Åmolecular sieves, until the following QC standards for water wereattained: a) <100 ppm for dichloromethane, toluene,N,N-dimethylformamide and tetrahydrofuran; b) <180 ppm for methanol,ethanol, 1,4-dioxane and diisopropylamine. For very sensitive reactions,solvents were further treated with metallic sodium, calcium hydride ormolecular sieves, and distilled just prior to use. Products weregenerally dried under vacuum before being carried on to furtherreactions or submitted for biological testing. Mass spectrometry data isreported from either liquid chromatography mass spectrometry (LCMS),atmospheric pressure chemical ionization (APCI) or gas chromatographymass spectrometry (GCMS) instrumentation. Chemical shifts for nuclearmagnetic resonance (NMR) data are expressed in parts per million (ppm,δ) referenced to residual peaks from the deuterated solvents employed.In some examples, chiral separations were carried out to separateenantiomers of certain compounds of the invention (in some examples, theseparated enantiomers may be designated as ENT-1 and ENT-2, according totheir order of elution). In some examples, the optical rotation of anenantiomer was measured using a polarimeter. According to its observedrotation data (or its specific rotation data), an enantiomer with aclockwise rotation was designated as the (+)-enantiomer and anenantiomer with a counter-clockwise rotation was designated as the(−)-enantiomer. Racemic compounds may be indicated by the presence of(+/−) adjacent to the structure; in these cases, indicatedstereochemistry represents the relative (rather than absolute)configuration of the compound's substituents.

Reactions proceeding through detectable intermediates were generallyfollowed by LCMS, and allowed to proceed to full conversion prior toaddition of subsequent reagents. For syntheses referencing procedures inother Examples or Methods, reaction conditions (reaction time andtemperature) may vary. In general, reactions were followed by thin-layerchromatography or mass spectrometry, and subjected to work-up whenappropriate. In cases where a drying agent is not specified, sodiumsulfate may be employed. Purifications may vary between experiments: ingeneral, solvents and the solvent ratios used for eluents/gradients werechosen to provide appropriate R_(f)s or retention times. All startingmaterials in these Preparations and Examples are either commerciallyavailable or can be prepared by methods known in the art or as describedherein.

The following are abbreviations which may appear in the experimentalprocedures described herein:

Abbreviations: 9-BBN=9-borabicyclo[3.3.1]nonane; BF₃.Et₂O=borontrifluoride diethyl etherate; Boc=tert-butoxycarbonyl; br=broad;n-BuLi=n-butyllithium; t-BuONa=sodium tert-butoxide;t-ButylXPhos=di-tert-butyl[2′,4′,6′-tri(propan-2-yl)biphenyl-2-yl]phosphane;Bz=benzoyl; CDCl₃=deuterochloroform; CD₃OD=deuteromethanol; d=doublet;dd=doublet of doublet; ddd=doublet of doublet of doublets;DBU=1,8-diazabicyclo[5.4.0]undec-7-ene; DCM=dichloromethane;DEPT=distortionless enhancement of polarization transfer;DMB=(2,4-dimethoxyphenyl)methyl; EDC orEDCl=1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride;EtOAc=ethyl acetate; EtOH=ethanol; g=gram; h=hour; H₂O=water;HATU=O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate; HPLC=high-performance liquid chromatography;Hz=hertz; K₂CO₃=potassium carbonate; KF=potassium fluoride; L=liter;LCMS=liquid chromatography mass spectrometry; m=multiplet; M=molar;MeOH=methanol; mg=milligram; MHz=megahertz; min=minutes; mL=milliliter;μL=microliter; mmol=millimole; μmol=micromole; Mo(CO)₆=molybdenumhexacarbonyl; mol=mole; N=normal; N₂=nitrogen; NaH=sodium hydride;NaHCO₃=sodium bicarbonate; NaOCl=sodium hypochlorite; NaOH=sodiumhydroxide; Na₂SO₄=sodium sulfate; NEt₃=triethylamine; NH₄Cl=ammoniumchloride; NMR=nuclear magnetic resonance; NOE=Nuclear Overhauser effect;Pd(Amphos)₂Cl₂=bis[di-tert-butyl(4-dimethylaminophenyl)phosphine]dichloropalladium(II);Pd₂(dba)₃=tris(dibenzylideneacetone)dipalladium(0);Pd(dppf)Cl₂=[1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II);Pd(dtbpf)Cl₂=[1,1′-bis(di-tert-butylphosphino)-ferrocene]dichloropalladium(II);Pd(PCy₃)₂Cl₂=dichlorobis(tricyclohexyl-phosphine)palladium(II);psi=pounds per square inch; q=quartet; rt=room temperature; s=singlet;T3P=2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide;TBAF=tetrabutylammonium fluoride; TEA=triethylamine;TEA.3HF=triethylamine trihydrofluoride; TFA=trifluoroacetic acid;THF=tetrahydrofuran; TLC=thin-layer chromatography; tr=triplet.

Preparation P1 Ethyl3-bromo-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-2-carboxylate (P1)

Step 1. Synthesis of ethyl 5-hydroxy-1H-pyrazole-3-carboxylate (C1)

Acetic acid (150 mL) was added drop-wise to a solution of sodium1,4-diethoxy-1,4-dioxobut-2-en-2-olate (30.0 g, 0.143 mol) in toluene(150 mL), and the mixture was stirred at room temperature for 30minutes, whereupon hydrazine monohydrochloride (85%, 17 g, 0.29 mol) wasadded. The reaction mixture was stirred for an additional 30 minutes atroom temperature and subsequently heated at 100° C. overnight. It wasthen concentrated in vacuo and extracted with ethyl acetate (500 mL);the organic layer was washed sequentially with saturated aqueous sodiumbicarbonate solution (200 mL) and saturated aqueous sodium chloridesolution (200 mL), dried over sodium sulfate, filtered, and concentratedunder reduced pressure to provide the product as a yellow solid. Yield:17 g, 0.11 mol, 77%. ¹H NMR (400 MHz, DMSO-d₆) δ 12.75 (br s, 1 H), 5.91(br s, 1 H), 4.24 (q, J=7 Hz, 2H), 1.27 (t, J=7 Hz, 3H).

Step 2. Synthesis of ethyl6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-2-carboxylate (C2)

Potassium carbonate (48.3 g, 349 mmol) was added to a solution of C1(13.65 g, 87.42 mmol) in acetonitrile (250 mL). The mixture was stirredat room temperature for 15 minutes, whereupon 1,3-dibromopropane (10 mL,98 mmol) was added drop-wise, and the reaction mixture was heated atreflux for 16 hours. It was then allowed to cool to room temperature andfiltered; the filtered solids were washed with acetonitrile (2×100 mL).The filtrate was concentrated in vacuo, and the residue was purified viachromatography on silica gel (Gradient: 50% to 95% ethyl acetate inheptane) to afford the product as an orange oil. Yield: 10.48 g, 53.4mmol, 61%. LCMS m/z 197.0 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 6.03 (s,1H), 4.39 (q, J=7.1 Hz, 2H), 4.34-4.30 (m, 2H), 4.26 (t, J=6.2 Hz, 2H),2.33-2.26 (m, 2H), 1.39 (t, J=7.1 Hz, 3H).

Step 3. Synthesis of ethyl3-bromo-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-2-carboxylate (P1)

N-Bromosuccinimide (6.00 g, 33.7 mmol) was added portion-wise to asolution of C2 (6.00 g, 30.6 mmol) in acetonitrile (100 mL). After thereaction mixture had been stirred at 50° C. for 1 hour, it was allowedto cool to room temperature, concentrated in vacuo, and partitionedbetween ethyl acetate (200 mL) and water (150 mL). The organic layer waswashed with water (150 mL) and with saturated aqueous sodium chloridesolution (100 mL), dried over magnesium sulfate, filtered, andconcentrated in vacuo. Silica gel chromatography (Gradient: 20% to 80%ethyl acetate in heptane) provided material that contained residualsuccinimide; this was dissolved in ethyl acetate (100 mL), washed withwater (2×100 mL) and with saturated aqueous sodium chloride solution(100 mL), dried over magnesium sulfate, filtered and concentrated underreduced pressure. The resulting yellow solid was triturated with pentaneto afford the product as a white powder. Yield: 6.00 g, 21.8 mmol, 71%.LCMS m/z 276.9 (bromine isotope pattern observed) [M+H]⁺. ¹H NMR (400MHz, CDCl₃) δ 4.44-4.40 (m, 2H), 4.42 (q, J=7.1 Hz, 2H), 4.26 (t, J=6.2Hz, 2H), 2.36-2.29 (rn, 2H), 1.41 (t, J=7.1 Hz, 3H).

Preparation P2Azetidin-1-yl(3-bromo-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-2-yl)methanone(P2)

A mixture of azetidine hydrochloride (2.46 g, 26.3 mmol) andN,N-diisopropylethylamine (3.72 g, 28.8 mmol) in methanol (15 mL) wasstirred at 20° C. for 20 minutes, whereupon P1 (1.1 g, 4.0 mmol) andcalcium chloride (444 mg, 4.00 mmol) were added. After the reactionmixture had been stirred at 50° C. for 18 hours, it was concentrated invacuo and purified using silica gel chromatography (Gradient: 0% to 100%ethyl acetate in petroleum ether). The product was isolated as a whitesolid. Yield: 900 mg, 3.14 mmol, 78%. ¹H NMR (400 MHz, CDCl₃) δ 4.44 (brdd, J=8.0, 7.5 Hz, 2H), 4.39 (dd, J=5.3, 5.3 Hz, 2H), 4.22-4.13 (m, 4H),2.37-2.26 (m, 4H).

Preparation P33-Bromo-N-cyclopropyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-2-carboxamide(P3)

A mixture of P1 (1.00 g, 3.64 mmol), cyclopropanamine (98%, 2.60 mL,36.8 mmol), and calcium chloride (404 mg, 3.64 mmol) in methanol (36 mL)was heated overnight at 50° C. Solvent was removed in vacuo, and theresidue was partitioned between water (50 mL) and ethyl acetate (175mL). The organic layer was dried over magnesium sulfate, filtered, andconcentrated under reduced pressure to provide the product as a whitesolid. Yield: 1.00 g, 3.49 mmol, 96%. ¹H NMR (400 MHz, CDCl₃) δ 6.81 (brs, 1H), 4.39 (dd, J=5.3, 5.2 Hz, 2H), 4.16 (t, J=6.2 Hz, 2H), 2.89-2.81(m, 1H), 2.35-2.27 (m, 2H), 0.86-0.79 (m, 2H), 0.64-0.58 (m, 2H).

Preparations P4 and P5 Ethyl(6S)-6-fluoro-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-2-carboxylate(P4) and Ethyl(6R)-6-fluoro-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-2-carboxylate(P5)

Step 1. Synthesis of 2-fluoropropane-1,3-diol (C3)

Lithium aluminum hydride (1 M solution in tetrahydrofuran; 53.3 mL, 53.3mmol) was added over 10 minutes to a 0° C. solution of dimethylfluoropropanedioate (5.00 g, 33.3 mmol) in tetrahydrofuran (210 mL).After 2 minutes of stirring at 0° C., the ice bath lo was removed andthe reaction mixture was allowed to warm to room temperature over 2hours, whereupon it was again cooled to 0° C. An aqueous solution ofL(+)-tartaric acid, potassium sodium salt (Rochelle salt; 2 N, 100 mL)was cautiously added, and the resulting mixture was stirred at roomtemperature overnight. Ethyl acetate was added, and the aqueous layerwas extracted three times with ethyl acetate; the combined organiclayers were dried over sodium sulfate, filtered, and concentrated invacuo to afford the product. Yield: 2.31 g, 24.6 mmol, 74%. ¹H NMR (400MHz, CD₃CN) δ 4.48 (d of quintets, J=48.9, 4.7 Hz, 1 H), 3.72-3.59 (m,4H), 2.95 (br s, 2H).

Step 2. Synthesis of 2-fluoropropane-1,3-diylbis(4-methylbenzenesulfonate) (C4)

4-Methylbenzenesulfonic anhydride (16.8 g, 51.5 mmol) was added to a 0°C. solution of C3 (2.31 g, 24.6 mmol) in dichloromethane (120 mL).Triethylamine (7.87 mL, 56.5 mmol) was then added over 1 minute, and thereaction mixture was stirred at 0° C. for 1 hour, whereupon it waswashed sequentially with saturated aqueous sodium bicarbonate solutionand 1 M hydrochloric acid, dried over sodium sulfate, filtered, andconcentrated in vacuo. The residue was treated with ethanol (50 mL),heated at reflux and then cooled in an ice bath. After the mixture hadbeen stirred at 0° C. for 20 minutes, it was filtered; the collectedmaterial was washed with cold ethanol to afford the product as a solid.Yield: 8.42 g, 20.9 mmol, 85%. ¹H NMR (400 MHz, CDCl₃) δ 7.78 (br d,J=8.2 Hz, 4H), 7.38 (br d, J=8.3 Hz, 4H), 4.82 (d of quintets, J=46.5,4.4 Hz, 1 H), 4.18 (br dd, J=20, 4.4 Hz, 4H), 2.48 (s, 6H).

Step 3. Synthesis of ethyl6-fluoro-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-2-carboxylate (C5)

A mixture of C4 (20 g, 50 mmol), C1 (8.2 g, 52 mmol), cesium carbonate(48.5 g, 149 mmol), and sodium iodide (7.5 g, 50 mmol) inN,N-dimethylformamide (150 mL) was heated at 100° C. for 2 hours. Water(1 L) and ethyl acetate (500 mL) were added, and the organic layer wasconcentrated in vacuo; silica gel chromatography (Gradient: 1% to 50%ethyl acetate in petroleum ether) provided the product as a white solid.Yield: 8.0 g, 37 mmol, 74%. ¹H NMR (400 MHz, CDCl₃) δ 6.10 (s, 1H),[5.32-5.27 (m) and 5.21-5.16 (m), J_(HF)=46 Hz, 1H], 4.67-4.54 (m, 2H),4.48-4.32 (m, 1H), 4.39 (q, J=7.1 Hz, 2H), 4.22 (br dd, J=36.6, 12.4 Hz,1H), 1.39 (t, J=7.1 Hz, 3H).

Step 4. Isolation of ethyl(6S)-6-fluoro-6,7-dihydro-5H-pyrazolo[5,1-b](1,3]oxazine-2-carboxylate(P4) and ethyl(6R)-6-fluoro-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-2-carboxylate(P5)

A racemic mixture of P4 and P5 (833 mg) was separated usingsupercritical fluid chromatography (Column: Phenomenex Lux Cellulose-4,5 μm; Mobile phase: 4:1 carbon dioxide/methanol). The first-elutingenantiomer was P4; this material exhibited a negative (−) rotation.Yield for the separation: 250 mg, 30%. The second-eluting enantiomer wasP5; this material exhibited a positive (+) rotation. Yield for theseparation: 241 mg, 29%. The indicated absolute configurations for P4and P5 were assigned based on X-ray structural analysis of P4 (seebelow); the crystal was obtained via recrystallization of P4 from ethylacetate and hexanes.

Single-Crystal X-Ray Structure Determination on P4

Data collection was performed on a Bruker APEX diffractometer at roomtemperature. Data collection consisted of omega and phi scans.

The structure was solved by direct methods using SHELX software suite inthe space group P2₁. The structure was subsequently refined by thefull-matrix least squares method. All non-hydrogen atoms were found andrefined using anisotropic displacement parameters.

All hydrogen atoms were placed in calculated positions and were allowedto ride on their carrier atoms. The final refinement included isotropicdisplacement parameters for all hydrogen atoms.

Analysis of the absolute structure using likelihood methods (Hooft,2008) was performed using PLATON (Spek, 2010). The results indicate thatthe absolute structure has been correctly assigned. The methodcalculates that the probability that the structure is correct is 100.0.The Hooft parameter is reported as 0.05 with an esd of 0.05.

The final R-index was 3.2%. A final difference Fourier revealed nomissing or misplaced electron density.

Pertinent crystal, data collection and refinement information issummarized in Table 1. Atomic coordinates, bond lengths, bond angles,and displacement parameters are listed in Tables 2-5.

SOFTWARE AND REFERENCES

-   SHELXTL, Version 5.1, Bruker AXS, 1997.-   PLATON, A. L. Spek, J. Appl. Cryst. 2003, 36, 7-13.-   MERCURY, C. F. Macrae, P. R. Edington, P. McCabe, E. Pidcock, G. P.    Shields, R. Taylor, M. Towler, and J. van de Streek, J. Appl. Cryst.    2006, 39, 453-457.-   OLEX2, O. V. Dolomanov, L. J. Bourhis, R. J. Gildea, J. A. K.    Howard, and H. Puschmann, J. App. Cryst. 2009, 42, 339-341.-   R. W. W. Hooft, L. H. Strayer, and A. L. Spek, J. Appl. Cryst. 2008,    41, 96-103.-   H. D. Flack, Acta Cryst. 1983, A39, 867-881.

TABLE 1 Crystal data and structure refinement for P4. Empirical formulaC₉H₁₁FN₂O₃ Formula weight 214.20 Temperature 273(2) K Wavelength 1.54178Å Crystal system Monoclinic Space group P2₁ Unit cell dimensions a =4.80380(10) Å α = 90° b = 7.4633(2) Å β = 94.3670(10)° c = 13.7774(4) Åγ = 90° Volume 492.52(2) Å³ Z 2 Density (calculated) 1.444 Mg/m³Absorption coefficient 1.045 mm⁻¹ F(000) 224 Crystal size 0.35 × 0.11 ×0.11 mm³ Theta range for data collection 3.22 to 70.13° Index ranges −5<= h <= 5, −8 <= k <= 9, −16 <= l <= 16 Reflections collected 16010Independent reflections 1802 [R(int) = 0.0503] Completeness to theta =70.13° 99.9% Absorption correction Empirical Refinement methodFull-matrix least-squares on F² Data/restraints/parameters 1802/1/137Goodness-of-fit on F² 1.077 Final R indices [I>2sigma(I)] R1 = 0.0323,wR2 = 0.0841 R indices (all data) R1 = 0.0332, wR2 = 0.0858 Absolutestructure parameter −0.05(18) Largest diff. peak and hole 0.159 and−0.133 e · Å⁻³

TABLE 2 Atomic coordinates (×10⁴) and equivalent isotropic displacementparameters (Å² × 10³) for P4. U(eq) is defined as one-third of the traceof the orthogonalized U^(ij) tensor. x y z U(eq) C(1) 2869(4) −1491(3)7276(1) 52(1) C(2) 1645(4) −2066(3) 6286(1) 46(1) C(3) 147(4) −566(3)5743(2) 51(1) C(4) 3604(3) 1401(2) 6434(1) 39(1) C(5) 5169(4) 2909(2)6614(1) 43(1) C(6) 6662(3) 2537(2) 7502(1) 39(1) C(7) 8652(3) 3753(2)8039(1) 42(1) C(8) 12019(4) 4130(3) 9355(2) 56(1) C(9) 13657(5) 2987(3)10063(2) 65(1) F(1) 3835(2) −2639(2) 5749(1) 63(1) N(1) 4179(3) 246(2)7173(1) 40(1) N(2) 6092(3) 914(2) 7850(1) 44(1) O(1) 1883(3) 980(2)5649(1) 53(1) O(2) 8933(3) 5300(2) 7807(1) 63(1) O(3) 10035(3) 2994(2)8794(1) 54(1)

TABLE 3 Bond lengths [Å] and angles [°] for P4. C(1)—N(1) 1.453(2)C(1)—C(2) 1.506(2) C(2)—F(1) 1.399(2) C(2)—C(3) 1.500(3) C(3)—O(1)1.436(2) C(4)—O(1) 1.346(2) C(4)—N(1) 1.347(2) C(4)—C(5) 1.366(2)C(5)—C(6) 1.397(2) C(6)—N(2) 1.339(2) C(6)—C(7) 1.476(2) C(7)—O(2)1.208(2) C(7)—O(3) 1.318(2) C(8)—O(3) 1.454(2) C(8)—C(9) 1.477(3)N(1)—N(2) 1.3542(19) N(1)—C(1)—C(2) 107.91(14) F(1)—C(2)—C(3) 108.37(14)F(1)—C(2)—C(1) 108.03(15) C(3)—C(2)—C(1) 112.25(17) O(1)—C(3)—C(2)112.63(13) O(1)—C(4)—N(1) 122.41(15) O(1)—C(4)—C(5) 129.34(16)N(1)—C(4)—C(5) 108.13(15) C(4)—C(5)—C(6) 103.57(15) N(2)—C(6)—C(5)112.84(15) N(2)—C(6)—C(7) 121.23(15) C(5)—C(6)—C(7) 125.93(15)O(2)—C(7)—O(3) 124.04(17) O(2)—C(7)—C(6) 122.39(17) O(3)—C(7)—C(6)113.56(15) O(3)—C(8)—C(9) 108.03(17) C(4)—N(1)—N(2) 112.03(14)C(4)—N(1)—C(1) 125.44(15) N(2)—N(1)—C(1) 122.49(14) C(6)—N(2)—N(1)103.44(13) C(4)—O(1)—C(3) 116.15(14) C(7)—O(3)—C(8) 116.06(15)

Symmetry transformations used to generate equivalent atoms.

TABLE 4 Anisotropic displacement parameters (Å² × 10³) for P4. Theanisotropic displacement factor exponent takes the form: −2π²[h²a*²U¹¹ + ... + 2 h k a* b* U¹²]. U¹¹ U²² U³³ U²³ U¹³ U¹² C(1) 68(1)43(1) 46(1) 5(1) 4(1) −23(1) C(2) 51(1) 41(1) 46(1) −2(1) 7(1) −12(1)C(3) 39(1) 48(1) 64(1) −5(1) −1(1) −7(1) C(4) 38(1) 36(1) 44(1) 2(1)1(1) −2(1) C(5) 47(1) 32(1) 50(1) 6(1) 1(1) −2(1) C(6) 40(1) 35(1) 42(1)0(1) 6(1) −4(1) C(7) 42(1) 36(1) 48(1) 0(1) 6(1) −5(1) C(8) 54(1) 47(1)66(1) −9(1) −9(1) −8(1) C(9) 75(1) 58(1) 59(1) −4(1) −13(1) −7(1) F(1)71(1) 53(1) 65(1) −7(1) 13(1) 13(1) N(1) 46(1) 35(1) 40(1) 3(1) 4(1)−9(1) N(2) 53(1) 38(1) 39(1) 2(1) −1(1) −12(1) O(1) 54(1) 44(1) 57(1)8(1) −16(1) −10(1) O(2) 78(1) 40(1) 70(1) 7(1) −9(1) −18(1) O(3) 59(1)40(1) 60(1) 2(1) −14(1) −11(1)

TABLE 5 Hydrogen coordinates (×10⁴) and isotropic displacementparameters (Å² × 10³) for P4. x y z U(eq) H(1A) 1411 −1407 7724 63 H(1B)4240 −2359 7531 63 H(2) 348 −3062 6358 55 H(3A) −508 −984 5099 61 H(3B)−1473 −228 6080 61 H(5) 5227 3939 6236 52 H(8A) 11036 5045 9693 67 H(8B)13247 4715 8926 67 H(9A) 14609 2080 9721 97 H(9B) 12428 2430 10490 97H(9C) 15001 3709 10437 97

Preparations P6 and P7 Ethyl(6S)-3-bromo-6-fluoro-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-2-carboxylate(P6) and Ethyl(6R)-3-bromo-6-fluoro-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-2-carboxylate(P7)

Step 1. Synthesis of ethyl3-bromo-6-fluoro-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-2-carboxylate(C6)

N-Bromosuccinimide (7.3 g, 41 mmol) was added to a solution of C5 (8.0g, 37 mmol) and acetic acid (0.5 mL) in dichloromethane (120 mL), andthe reaction mixture was stirred at room temperature for 3 hours. Afterremoval of solvents in vacuo, the residue was purified via silica gelchromatography (Gradient: 9% to 50% ethyl acetate in petroleum ether) toafford the product as a white solid. Yield: 8.5 g, 29 mmol, 78%. LCMSm/z 294.8 (bromine isotope pattern observed) [M+H]⁺. ¹H NMR (400 MHz,CDCl₃) δ [5.37-5.31 (m) and 5.25-5.20 (m), J_(HF)=45 Hz, 1H], 4.79-4.70(m, 1H), 4.66-4.55 (m, 1H), 4.48-4.32 (m, 1H), 4.43 (q, J=7.2 Hz, 2H),4.29 (br dd, J=36.8, 12.9 Hz, 1H), 1.42 (t, J=7.2 Hz, 3H).

Step 2. Synthesis of ethyl(6S)-3-bromo-6-fluoro-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-2-carboxylate(P6) and ethyl(6R)-3-bromo-6-fluoro-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-2-carboxylate(P7)

A racemic mixture of P6 and P7 (1.0 g) was separated using supercriticalfluid chromatography (Column: Phenomenex Lux Cellulose-3, 5 μm; Mobilephase: 4:1 carbon dioxide/methanol). The first-eluting enantiomer wasP6; this material exhibited a negative (−) rotation. Yield for theseparation: ˜500 mg, ˜50%. ¹H NMR (400 MHz, CDCl₃) δ [5.36-5.32 (m) and5.25-5.21 (m), J_(HF)=45 Hz, 1H], 4.79-4.70 (m, 1H), 4.67-4.56 (m, 1H),4.48-4.33 (m, 1H), 4.43 (q, J=7.1 Hz, 2H), 4.29 (br dd, J=36.9, 12.9 Hz,1H), 1.42 (t, J=7.1 Hz, 3H). The second-eluting enantiomer was P7; thismaterial exhibited a positive (+) rotation. Yield for the separation:˜500 mg, ˜50%. ¹H NMR (400 MHz, CDCl₃) δ [5.36-5.32 (m) and 5.25-5.20(m), J_(HF)=45 Hz, 1H], 4.79-4.70 (m, 1H), 4.67-4.56 (m, 1H), 4.49-4.32(m, 1H), 4.43 (q, J=7.1 Hz, 2H), 4.29 (br dd, J=36.8, 12.8 Hz, 1H), 1.42(t, J=7.1 Hz, 3H). The absolute configurations of P6 and P7 wereassigned via correlation with P5 (see Alternate synthesis of P7 below).

Alternate Synthesis of ethyl(6R)-3-bromo-6-fluoro-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-2-carboxylate(P7)

N-Bromosuccinimide (229 mg, 1.29 mmol) was added to a solution of P5(250 mg, 1.17 mmol) in dichloromethane (5 mL). A few drops of aceticacid were added, and the reaction mixture was stirred overnight at roomtemperature. It was then diluted with dichloromethane, washed withaqueous sodium bicarbonate solution, dried over magnesium sulfate,filtered, and concentrated in vacuo. Chromatography on silica gel(Gradient: 0% to 100% ethyl acetate in heptane) afforded the product asa solid. This material exhibited a positive (+) rotation, confirming itas P7. Yield: 259 mg, 0.884 mmol, 76%. LCMS m/z 315.1 (bromine isotopepattern observed) [M+Na⁺]. ¹H NMR (400 MHz, CDCl₃) δ [5.36-5.32 (m) and5.25-5.20 (m), J_(HF)=45 Hz, 1H], 4.78-4.68 (m, 1H), 4.65-4.54 (m, 1H),4.48-4.32 (m, 1H), 4.41 (q, J=7.1 Hz, 2H), 4.29 (br dd, J=37.1, 12.8 Hz,1H), 1.40 (t, J=7.1 Hz, 3H).

Preparations P8 and P9 Ethyl5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-2-carboxylate (P8)and Ethyl7-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-2-carboxylate (P9)

1,3-Dibromobutane (5.8 g, 27 mmol) was added to a suspension of C1 (4.0g, 26 mmol) and potassium carbonate (14.1 g, 102 mmol) in acetonitrile(100 mL), and the reaction mixture was heated at reflux overnight. Afterit had cooled to room temperature, it was filtered, and the collectedsolids were washed with acetonitrile (3×30 mL). The combined filtrateswere concentrated in vacuo to afford a mixture of P8 and P9 as a yellowoil. By ¹H NMR, this was a roughly 2-3 to 1 mixture. ¹H NMR (400 MHz,CDCl₃), minor component, presumed to be P8: δ 6.00 (s, 1H), 4.42-4.14(m, 5H), 2.25-2.17 (m, 1H), 2.15-2.06 (m, 1H), 1.48 (d, J=6.3 Hz, 3H),1.39 (t, J=7.1 Hz, 3H); major component, presumed to be P9: δ 6.00 (s,1H), 4.49-4.22 (m, 5H), 2.37 (dddd, J=14.4, 7.4, 5.6, 3.1 Hz, 1H), 2.01(dddd, J=14.4, 7.8, 6.6, 3.1 Hz, 1H), 1.64 (d, J=6.5 Hz, 3H), 1.38 (t,J=7.1 Hz, 3H). This mixture was subjected to silica gel chromatography(Gradient: 17% to 67% ethyl acetate in petroleum ether) to afford theproducts. The indicated regiochemistry was assigned on the basis of NMRstudies carried out on bromo derivatives C7 and C9 (see below). Yield ofP8: 0.9 g, 4 mmol, 15%. Yield of P9: 1.7 g, 8.1 mmol, 31%.

Preparation P103-(4-Chlorophenyl)-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-2-carboxylicacid (P10)

Step 1. Synthesis of ethyl3-bromo-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-2-carboxylate(C7)

A solution of P8 (0.84 g, 4.0 mmol) and N-bromosuccinimide (0.86 g, 4.8mmol) in tetrachloromethane (30 mL) was stirred at 60° C. for 3 hours,whereupon it was partitioned between water (30 mL) and dichloromethane(50 mL). The organic layer was washed with saturated aqueous sodiumchloride solution (30 mL), dried over sodium sulfate, filtered, andconcentrated in vacuo. Silica gel chromatography (Gradient: 9% to 50%ethyl acetate in petroleum ether) afforded the product as a yellowsolid. Yield: 0.80 g, 2.8 mmol, 70%. The position of the methyl groupwas established via examination of the ¹³C NMR spectrum of C7 incomparison with the ¹³C NMR and DEPT spectra of C9. ¹H NMR (400 MHz,CDCl₃) δ 4.52-4.43 (m, 1H), 4.42 (q, J=7.1 Hz, 2H), 4.32 (ddd, half ofABXY pattern, J=12.9, 5.8, 2.9 Hz, 1H), 4.19 (ddd, half of ABXY pattern,J=12.8, 11.0, 5.4 Hz, 1H), 2.29-2.21 (m, 1H), 2.19-2.05 (m, 1H), 1.55(d, J=6.3 Hz, 3H), 1.41 (t, J=7.1 Hz, 3H).

Step 2. Synthesis of ethyl3-(4-chlorophenyl)-5-methyl-6,7-dihydro-5H-pyrazoto[5,1-b][1,3]oxazine-2-carboxylate(C8)

To a solution of C7 (332 mg, 1.15 mmol) in 1,4-dioxane (10 mL) and water(2.5 mL) were added (4-chlorophenyl)boronic acid (187 mg, 1.20 mmol),cesium carbonate (560 mg, 1.72 mmol), anddichlorobis(tricyclohexylphosphine)palladium(II) (39 mg, 53 μmol). Thereaction mixture was degassed by sparging with nitrogen and then stirredat 110° C. overnight, whereupon it was partitioned between water (10 mL)and ethyl acetate (60 mL). The organic layer was washed with saturatedaqueous sodium chloride solution (20 mL), dried over sodium sulfate,filtered, and concentrated in vacuo; silica gel chromatography(Gradient: 9% to 50% ethyl acetate in petroleum ether) afforded theproduct as a yellow solid. This material was impure, as assessed by ¹HNMR analysis. Yield: 0.38 g, ˜60% purity, 0.7 mmol, 60%. ¹H NMR (400MHz, CDCl₃), characteristic peaks: δ 7.38 (br AB quartet, J_(AB)=8.6 Hz,Δ□_(AB)=33.7 Hz, 4H), 4.35 (q, J=7.1 Hz, 2H), 1.49 (d, J=6.3 Hz, 3H),1.34 (t, J=7.2 Hz, 3H).

Step 3. Synthesis of3-(4-chlorophenyl)-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-2-carboxylicacid (P10)

To a solution of C8 (from the previous step, of approximately 60%purity; 250 mg, 0.47 mmol) in methanol (6 mL) was added lithiumhydroxide monohydrate (79 mg, 1.9 mmol), and the reaction mixture wasstirred at 60° C. overnight. It was then acidified to a pH ofapproximately 6 via addition of concentrated hydrochloric acid. Removalof volatiles in vacuo afforded the crude product (350 mg), which wasused in Example 9 without additional purification. LCMS m/z 292.7(chlorine isotope pattern observed) [M+H]⁺.

Preparation P113-(4-Chlorophenyl)-7-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-2-carboxylicacid (P11)

Step 1. Synthesis of ethyl3-bromo-7-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-2-carboxylate(C9)

Conversion of P9 to C9 was carried out using the method described forsynthesis of C7 in Preparation P10; the product was isolated as a yellowsolid. The position of the methyl group was established via examinationof the ¹³C NMR and DEPT spectra of C9 in comparison with the ¹³C NMRspectrum of C7. Yield: 1.1 g, 3.8 mmol, 76%. ¹H NMR (400 MHz, CDCl₃) δ4.51-4.40 (m, 2H), 4.42 (q, J=7.2 Hz, 2H), 4.36 (ddd, J=11.3, 7.9, 3.1Hz, 1H), 2.40 (dddd, J=14.6, 7.4, 5.4, 3.1 Hz, 1H), 2.10-2.00 (m, 1H),1.64 (d, J=6.4 Hz, 3H), 1.41 (t, J=7.1 Hz, 3H).

Step 2. Synthesis of ethyl3-(4-chlorophenyl)-7-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-2-carboxylate(C10)

Conversion of C9 to the product was carried out using the methoddescribed for synthesis of C8 in Preparation P10. The product wasobtained as a yellow solid of approximately 60% purity via ¹H NMRanalysis. Yield: 1.2 g, ˜60% purity, 2 mmol, 50%. ¹H NMR (400 MHz,CDCl₃), characteristic product peaks only: δ 7.36 (br AB quartet,J_(AB)=8.7 Hz, Δ□_(AB)=24.2 Hz, 4H), 4.34 (q, J=7.2 Hz, 2H), 1.68 (d,J=6.5 Hz, 3H), 1.31 (t, J=7.2 Hz, 3H).

Step 3. Synthesis of3-(4-chlorophenyl)-7-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-2-carboxylicacid (P11)

To a solution of C10 (from the previous step, of approximately 60%purity; 320 mg, 0.6 mmol) in methanol (6 mL) was added lithium hydroxidemonohydrate (126 mg, 3.00 mmol), and the reaction mixture was stirred at60° C. overnight. It was then acidified to a pH of approximately 6 viaaddition of concentrated hydrochloric acid. Removal of volatiles invacuo afforded the crude product (500 mg), which was used in Example 10without additional purification. LCMS m/z 292.8 (chlorine isotopepattern observed) [M+H]⁺.

Preparation P123-Bromo-N-cyclopropyl-6,6-difluoro-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-2-carboxamide(P12)

Step 1. Synthesis of 2-hydroxypropane-1,3-diylbis(4-methylbenzenesulfonate) (C11)

p-Toluenesulfonyl chloride (747 g, 3.92 mol) was added portion-wise to a0° C. solution of propane-1,2,3-triol (180 g, 1.95 mol) and4-(dimethylamino)pyridine (24 g, 0.20 mol) in pyridine (400 mL) anddichloromethane (1.5 L). After the reaction mixture had been stirred atroom temperature overnight, it was treated with ice water, and the pHwas adjusted to 3 via addition of concentrated hydrochloric acid. Themixture was extracted with dichloromethane (3×1 L), and the combinedorganic layers were dried, filtered, and concentrated in vacuo. Silicagel chromatography (Gradient: 9% to 33% ethyl acetate in petroleumether) provided the product as a colorless oil, which was impure by ¹HNMR analysis. Yield: 280 g, <699 mmol, <36%. ¹H NMR (400 MHz, CDCl₃),product peaks only: δ 7.77 (d, J=8.3 Hz, 4H), 7.36 (d, J=8.0 Hz, 4H),4.10-4.01 (m, 5H), 2.47 (s, 6H).

Step 2. Synthesis of 2-oxopropane-1,3-diyl bis(4-methylbenzenesulfonate)(C12)

Dess-Martin periodinane[1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one] (9.50 g,22.4 mmol) was added to a solution of C11 (3.0 g, 7.5 mmol) indichloromethane (100 mL), and the reaction mixture was stirred at roomtemperature overnight. Saturated aqueous sodium bicarbonate solution andsaturated aqueous sodium thiosulfate solution were added, and theresulting mixture was extracted with dichloromethane. The combinedorganic layers were dried, filtered, and concentrated in vacuo; silicagel chromatography (Gradient: 9% to 50% ethyl acetate in petroleumether) afforded the product as a white solid. Yield: 2.0 g, 5.0 mmol,67%. ¹H NMR (400 MHz, CDCl₃) δ 7.81 (d, J=8.3 Hz, 4H), 7.39 (d, J=8.1Hz, 4H), 4.71 (s, 4H), 2.48 (s 6H).

Step 3. Synthesis of 2,2-difluoropropane-1,3-diylbis(4-methylbenzenesulfonate) (C13)

A solution of C12 (1.2 g, 3.0 mmol) in dichloromethane (30 mL) wasslowly added to (diethylamino)sulfur trifluoride (2.4 g, 15 mmol) at 0°C. The reaction mixture was stirred at 40° C. for 6 hours, whereupon itwas slowly treated with saturated aqueous sodium bicarbonate solution.The resulting mixture was extracted with dichloromethane, and theorganic layer was dried, filtered, and concentrated in vacuo. Theresidue was purified via silica gel chromatography (Gradient: 9% to 50%ethyl acetate in petroleum ether), providing the product as a lightyellow solid. Yield: 550 mg, 1.3 mmol, 43%. LCMS m/z 442.9 [M+Na⁺]. ¹HNMR (400 MHz, CDCl₃) δ 7.78 (br d, J=8.3 Hz, 4H), 7.39 (br d, J=8.0 Hz,4H), 4.18 (t, J_(HF)=11.4 Hz, 4H), 2.48 (s, 6H).

Step 4. Synthesis of ethyl6,6-difluoro-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-2-carboxylate(C14)

A mixture of C13 (460 mg, 1.1 mmol), C1 (600 mg, 3.8 mmol), cesiumcarbonate (1.1 g, 3.4 mmol), and sodium iodide (140 mg, 0.93 mmol) inN,N-dimethylformamide (13 mL) was heated to 100° C. for 3 hours. Thereaction mixture was then diluted with water (30 mL) and extracted withethyl acetate (3×15 mL). The combined organic layers were concentratedunder reduced pressure and purified via silica gel chromatography(Gradient: 0% to 50% ethyl acetate in petroleum ether); the product wasisolated as a white solid. Yield: 220 mg, 0.95 mmol, 86%. ¹H NMR (400MHz, CDCl₃) δ 6.15 (s, 1H), 4.59 (br t, J_(HF)=12.4 Hz, 2H), 4.40 (q,J=7.2 Hz, 2H), 4.36 (br t, J_(HF)=10.4 Hz, 2H), 1.40 (t, J=7.2 Hz, 3H).

Step 5. Synthesis of ethyl3-bromo-6,6-difluoro-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-2-carboxylate(C15)

A mixture of C14 (200 mg, 0.86 mmol) and N-bromosuccinimide (178 mg,1.00 mmol) in dichloromethane (30 mL) was stirred at room temperaturefor 16 hours. The reaction mixture was then diluted with dichloromethane(50 mL), washed with saturated aqueous sodium chloride solution, driedover sodium sulfate, filtered, and concentrated in vacuo to afford theproduct as a yellow solid. Yield: 230 mg, 0.74 mmol, 86%.

Step 6. Synthesis of3-bromo-N-cyclopropyl-6,6-difluoro-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-2-carboxamide(P12)

A mixture of C15 (290 mg, 0.93 mmol), cyclopropanamine (2 mL), andcalcium chloride (100 mg, 0.90 mmol) in methanol (20 mL) was heated to50° C. for 3 hours. The reaction mixture was then concentrated underreduced pressure; the residue was diluted with dichloromethane (80 mL),washed sequentially with water (15 mL) and saturated aqueous sodiumchloride solution, dried over sodium sulfate, filtered, and concentratedin vacuo to provide the product as a yellow solid. Yield: 250 mg, 0.78mmol, 84%. ¹H NMR (400 MHz, CDCl₃) δ 4.50 (t, J_(HF)=11.9 Hz, 2H), 4.43(t, J_(HF)=10.4 Hz, 2H), 2.90-2.81 (m, 1 H), 0.89-0.80 (m, 2H),0.66-0.58 (m, 2H).

EXAMPLE 1

Azetidin-1-yl[3-(4-chloro-2-methylphenyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-2-yl]methanone(1)

To a solution of P2 (100 mg, 0.35 mmol) in 1,4-dioxane (20 mL) and water(0.5 mL) were added (4-chloro-2-methylphenyl)boronic acid (71 mg, 0.42mmol),bis[di-tert-butyl(4-dimethylaminophenyl)phosphine]dichloropalladium(II)[Pd(Amphos)₂Cl₂; 13 mg, 18 μmol] and cesium fluoride (161 mg, 1.06mmol), and the reaction mixture was stirred at 100° C. for 15 hours. Itwas then filtered, and the filtrate was concentrated in vacuo; theresidue was purified by reversed phase HPLC (Column: Phenomenex GeminiC18, 8 μm; Mobile phase A: aqueous ammonia, pH 10; Mobile phase B:acetonitrile; Gradient: 38% to 58% B) to provide the product as a whitesolid. Yield: 13.3 mg, 40 μmol, 11%. LCMS m/z 354.1 (chlorine isotopepattern observed) [M+Na⁺]. ¹H NMR (400 MHz, CDCl₃) δ 7.22 (br s, 1H),7.18-7.13 (m, 2H), 4.34 4.28 (m, 2H), 4.28-4.17 (m, 4H), 4.11-4.04 (m,2H), 2.37-2.28 (m, 2H), 2.27-2.17 (m, 2H), 2.20 (s, 3H).

EXAMPLE 23-(4-Chloro-2-methylphenyl)-N-cyclopropyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-2-carboxamide(2)

A flask containing toluene (25 mL) was evacuated and charged withnitrogen. Addition of P3 (250 mg, 0.874 mmol) and(4-chloro-2-methylphenyl)boronic acid (298 mg, 1.75 mmol) was carriedout using the same degassing procedure after each addition. A solutionof cesium fluoride (664 mg, 4.37 mmol) in water (4.4 mL) was added,followed by a solution ofbis[di-tert-butyl(4-dimethylaminophenyl)phosphine]dichloropalladium(II)(77.2 mg, 0.109 mmol) in 1,2-dichloroethane (2.2 mL), and the reactionmixture was heated to 100° C. for 16 hours. It was then concentrated invacuo and subjected to chromatography on silica gel (Eluent: ethylacetate), followed by reversed phase HPLC (Column: Phenomenex LunaC18(2), 5 μm; Mobile phase A: 0.1% formic acid in water; Mobile phase B:0.1% formic acid in methanol; Gradient: 30% to 80% B). The product wasisolated as a solid. Yield: 67.5 mg, 0.203 mmol, 23%. LCMS m/z 332.1(chlorine isotope pattern observed) [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ7.20 (br s, 1H), 7.15 (AB quartet, upfield doublet is broadened,J_(AB)=8.2 Hz, Δ□_(AB)=10.7 Hz, 2H), 6.79 (br s, 1H), 4.27 (dd, J=5.1,5.1 Hz, 2H), 4.20 (t, J=6.2 Hz, 2H), 2.79-2.70 (m, 1H), 2.33-2.24 (m,2H), 2.17 (s, 3H), 0.78-0.71 (m, 2H), 0.56-0.49 (m, 2H).

EXAMPLE 3Azetidin-1-yl[3-(4-chloro-2,5-difluorophenyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-2-yl]methanone(3)

Step 1. Synthesis of2-(4-chloro-2,5-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(C16)

A mixture of 1-bromo-4-chloro-2,5-difluorobenzene (9.00 g, 39.6 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (15.1 g, 59.5mmol), and potassium acetate (7.8 g, 80 mmol) in 1,4-dioxane (80 mL) wasdegassed via sparging with nitrogen for 2 minutes.[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.5 g, 2.0mmol) was then added, and the reaction mixture was stirred at 100° C.for 18 hours. It was then filtered; the filtrate was concentrated invacuo and subjected to silica gel chromatography (Gradient: 0% to 10%ethyl acetate in petroleum ether), affording the product as a yellowsolid. Yield: 6.1 g, 2.2 mmol, 56%. ¹H NMR (400 MHz, CDCl₃) δ 7.48 (dd,J=8.8, 4.9 Hz, 1H), 7.12 (dd, J=8.0, 5.6 Hz, 1H), 1.36 (s, 12H).

Step 2. Synthesis ofazetidin-1-yl[3-(4-chloro-2,5-difluorophenyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-2-yl]methanone(3)

A mixture of P2 (1.8 g, 6.3 mmol), C16 (4.32 g, 15.7 mmol), and cesiumcarbonate (4.10 g, 12.6 mmol) in 1,4-dioxane (20 mL) was degassed viasparging with nitrogen for 2 minutes.[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (460 mg,0.63 mmol) was then added, and the reaction mixture was stirred at 100°C. for 18 hours. After water (60 mL) and dichloromethane (60 mL) hadbeen added, the mixture was filtered, and the filtrate was extractedwith dichloromethane (3×40 mL). The combined organic layers were washedwith saturated aqueous sodium chloride solution, dried over sodiumsulfate, filtered, and concentrated in vacuo; reversed phase HPLC(Column: Phenomenex Gemini, 10 μm; Mobile phase A: 0.05% aqueoushydrochloric acid; Mobile phase B: acetonitrile; Gradient: 30% to 70% B)provided the product as a light yellow solid. Yield: 700 mg, 2.0 mmol,32%. LCMS m/z 354.1 (chlorine isotope pattern observed) [M+H]⁺. ¹H NMR(400 MHz, CDCl₃) δ 7.26 (dd, J=9.4, 6.4 Hz, 1H), 7.13 (dd, J=8.8, 6.3Hz, 1H), 4.41 (br dd, J=7.8, 7.5 Hz, 2H), 4.36 (dd, J=5.3, 5.3 Hz, 2H),4.22 (t, J=6.3 Hz, 2H), 4.14 (br dd, J=7.8, 7.8 Hz, 2H), 2.38-2.25 (m,4H).

EXAMPLE 4Azetidin-1-yl[3-(4-chloro-2,3-difluorophenyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-2-yl]methanone(4)

Step 1. Synthesis of ethyl3-(4-chloro-2,3-difluorophenyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-2-carboxylate(C18)

To a solution of2-(4-chloro-2,3-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(C17; this material was prepared using the method described forsynthesis of C16 in Example 3, except that it was used crude and inexcess) in 1,4-dioxane (8 mL) and water (2 mL) were added P1 (150 mg,0.545 mmol), dichlorobis(tricyclohexylphosphine)palladium(II) (20 mg, 27μmol), and cesium carbonate (355 mg, 1.09 mmol). The reaction mixturewas stirred at 100° C. overnight, whereupon it was concentrated in vacuoand purified via silica gel chromatography, providing the product as ayellow solid. Yield: 24.1 mg, 70.3 μmol, 13%. LCMS m/z 342.9 (chlorineisotope pattern observed) [M+H]⁺.

Step 2. Synthesis ofazetidin-1-yl[3-(4-chloro-2,3-difluorophenyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-2-yl]methanone(4)

Azetidine hydrochloride (37.6 mg, 0.402 mmol),N,N-diisopropylethylamine, and calcium chloride (22.2 mg, 0.200 mmol)were added to a solution of C18 (35 mg, 0.10 mmol) in methanol (10 mL),and the reaction mixture was stirred at 50° C. overnight. After removalof solvent in vacuo, the residue was purified using reversed phase HPLC(Column: Phenomenex Synergi C18, 4 μm; Mobile phase A: 0.225% formicacid in water; Mobile phase B: methanol; Gradient: 40% to 60% B) toafford the product as a white solid. Yield: 11.2 mg, 31.6 μmol, 32%.LCMS m/z 354.2 (chlorine isotope pattern observed) [M+H]⁺. ¹H NMR (400MHz, CDCl₃) δ 7.21-7.10 (m, 2H), 4.46-4.37 (m, 2H), 4.36 (dd, J=5.4, 4.9Hz, 2H), 4.23 (t, J=6.2 Hz, 2H), 4.18-4.10 (m, 2H), 2.39-2.25 (m, 4H).

EXAMPLE 53-(4-Cyano-5-fluoro-2-methylphenyl)-N-cyclopropyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-2-carboxamide(5)

Step 1. Synthesis of2-fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile(C19)

4-Bromo-2-fluoro-5-methylbenzonitrile (600 mg, 2.8 mmol) was convertedto the product using the method described for synthesis of C16 inExample 3. In this case, silica gel chromatography was carried out usinga gradient of 0% to 30% ethyl acetate in petroleum ether; the productwas obtained as a white solid. Yield: 500 mg, 1.9 mmol, 68%. ¹H NMR (400MHz, CDCl₃) δ 7.56 (d, J=9.4 Hz, 1 H), 7.38 (d, J=5.9 Hz, 1 H), 2.51 (s,3H), 1.36 (s, 12H).

Step 2. Synthesis of3-(4-cyano-5-fluoro-2-methylphenyl)-N-cyclopropyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-2-carboxamide(5)

[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (96 mg, 0.13mmol) was added to a mixture of P3 (750 mg, 2.62 mmol), C19 (1.03 g,3.94 mmol), and cesium carbonate (723 mg, 2.22 mmol) in 1,4-dioxane (20mL) and water (2 mL). After the reaction had been stirred at 100° C. for16 hours, it was concentrated in vacuo, dissolved in ethyl acetate (10mL) and washed with water (5 mL). The organic layer was dried oversodium sulfate, filtered, and concentrated under reduced pressure;silica gel chromatography (Gradient: 20% to 40% ethyl acetate inpetroleum ether) afforded the product as a white solid. Yield: 381.4 mg,1.120 mmol, 43%. LCMS m/z 340.9 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.43(d, J=6.5 Hz, 1H), 7.11 (d, J=9.7 Hz, 1H), 6.90 (br s, 1H), 4.34 (dd,J=5.3, 5.1 Hz, 2H), 4.22 (dd, J=6.3, 6.2 Hz, 2H), 2.79-2.72 (m, 1H),2.39-2.30 (m, 2H), 2.18 (s, 3H), 0.82-0.75 (m, 2H), 0.61-0.54 (m, 2H).

EXAMPLE 6(6S)-3-(4-Chloro-2-methylphenyl)-N-cyclopropyl-6-fluoro-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-2-carboxamide(6)

Step 1. Synthesis of ethyl(6S)-3-(4-chloro-2-methylphenyl)-6-fluoro-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-2-carboxylate(C20)

To a degassed mixture of 1,4-dioxane (5 mL) and water (0.5 mL) wereadded P6 (2.50 g, 8.53 mmol), (4-chloro-2-methylphenyl)boronic acid(1.60 g, 9.39 mmol), cesium carbonate (5.56 g, 17.1 mmol), and[1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (278mg, 0.426 mmol). The reaction vessel was evacuated and charged withnitrogen. This evacuation cycle was repeated twice, and then thereaction was allowed to proceed at room temperature for 3 hours. Solventwas removed in vacuo, and the residue was chromatographed on silica gel(Eluent: 1:1 ethyl acetate/heptane) to provide the product. Yield: 2.1g, 6.2 mmol, 73%. LCMS m/z 339.4 (chlorine isotope pattern observed)[M+H]⁺. ¹H NMR (400 MHz, CDCl₃), characteristic peaks: δ 7.24 (br s,1H), 7.17 (br dd, half of ABX pattern, J=8.2, 2.0 Hz, 1H), 7.13 (br d,half of AB quartet, J=8.2 Hz, 1H), [5.34-5.29 (m) and 5.23-5.18 (m),J_(HF)=45 Hz, 1H], 4.30-4.13 (m, 3H), 2.16 (s, 3H), 1.23 (t, J=7.1 Hz,3H).

Step 2. Synthesis of(6S)-3-(4-chloro-2-methylphenyl)-6-fluoro-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-2-carboxylicacid (C21)

Potassium hydroxide (13 mmol) was added to a solution of C20 (2.2 g, 6.5mmol) in methanol (10 mL), and the reaction mixture was stirredovernight at room temperature. It was then cooled in an ice bath,acidified to a pH of 4-5 via addition of hydrogen chloride solution, andconcentrated in vacuo. This material was used without purification inthe following step. LCMS m/z 311.3 (chlorine isotope pattern observed)[M+H]⁺.

Step 3. Synthesis of(6S)-3-(4-chloro-2-methylphenyl)-N-cyclopropyl-6-fluoro-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-2-carboxamide(6)

A solution of C21 (from the previous step, ≤6.5 mmol) andcyclopropanamine (600 mg, 10.5 mmol) in dichloromethane (50 mL) wastreated with N,N-diisopropylethylamine (2.49 mL, 14.3 mmol).2,4,6-Tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (4.55 g,14.3 mmol, as a 50% solution in ethyl acetate) was then added, and thereaction mixture was stirred at room temperature overnight. It was thenwashed sequentially with saturated aqueous sodium bicarbonate solution(10 mL) and saturated aqueous sodium chloride solution (10 mL), dried,filtered, and concentrated in vacuo. One portion of the resultingmaterial was subjected to supercritical fluid chromatography (Column:Princeton 4-Ethylpyridine, 5 μm; Mobile phase: 4:1 carbondioxide/ethanol), affording the product as a white solid (0.89 g). Thismaterial was crystalline via powder X-ray diffraction. The remainder wasrecrystallized from methanol to afford additional product (0.97 g).Combined yield over 2 steps: 1.86 g, 5.32 mmol, 82%. LCMS m/z 350.4(chlorine isotope pattern observed) [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ7.24 (br s, 1 H), 7.21 (d, half of AB quartet, J=8.2 Hz, 1 H), 7.17 (brdd, half of ABX pattern, J=8.2, 1.4 Hz, 1 H), 6.75 (br s, 1 H),[5.34-5.29 (m) and 5.23-5.18 (m), J_(HF)=45 Hz, 1H], 4.65-4.49 (m, 2H),4.40 (ddd, half of ABXY pattern, J=36.7, 14.2, 3.3 Hz, 1H), 4.21 (dd,J=36.9, 12.7 Hz, 1H), 2.81-2.72 (m, 1H), 2.19 (s, 3H), 0.80-0.73 (m,2H), 0.57-0.50 (m, 2H).

EXAMPLE 7(6S)-3-(4-Chloro-2,5-difluorophenyl)-N-cyclopropyl-6-fluoro-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-2-carboxamide(7)

Step 1. Synthesis of(6S)-3-bromo-N-cyclopropyl-6-fluoro-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-2-carboxamide(C22)

Trimethylaluminum (2 M solution in toluene; 8 mL, 16 mmol) was added toa solution of P6 (2.5 g, 8.5 mmol) and cyclopropanamine (8 mL) intoluene (50 mL), and the reaction mixture was heated at 80° C. for 2hours. Water (200 mL) was added, and the resulting mixture was extractedwith ethyl acetate (3×100 mL); the combined organic layers were driedand filtered. After the filtrate had been treated with silica gel, itwas filtered and the filtrate was concentrated in vacuo, providing theproduct as a yellow solid. Yield: 2.30 g, 7.56 mmol, 89%. ¹H NMR (400MHz, CDCl₃) δ 6.81 (br s, 1H), [5.36-5.30 (m) and 5.25-5.18 (m),J_(HF)=45.2 Hz, 1H], 4.77-4.67 (m, 1H), 4.53-4.42 (m, 1H), 4.42-4.21 (m,2H), 2.88-2.80 (m, 1H), 0.86-0.79 (m, 2H), 0.64-0.58 (m, 2H).

Step 2. Synthesis of(6S)-3-(4-chloro-2,5-difluorophenyl)-N-cyclopropyl-6-fluoro-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-2-carboxamide(7)

A mixture of C22 (600 mg, 1.97 mmol), C16 (850 mg, 3.10 mmol), andcesium carbonate (1.3 g, 4.0 mmol) in 1,4-dioxane (15 mL) and water (1.5mL) was degassed via sparging with nitrogen for 2 minutes, whereupon[1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (30 mg,46 μmol) was added. After the reaction mixture had been heated at 100°C. for 3 hours, it was filtered and concentrated in vacuo. Purificationusing reversed phase HPLC (Column: YMC-Triart C18, 5 μm; Mobile phase A:0.225% formic acid in water; Mobile phase B: acetonitrile; Gradient: 42%to 62% B) afforded the product as a yellow solid. Yield: 257 mg, 0.691mmol, 35%. LCMS m/z 371.9 (chlorine isotope pattern observed) [M+H]⁺. ¹HNMR (400 MHz, CDCl₃) δ 7.28 (dd, J=9.0, 6.5 Hz, 1H, assumed; partiallyobscured by solvent peak), 7.15 (dd, J=8.6, 6.4 Hz, 1H), 6.87 (br s,1H), [5.37-5.29 (m) and 5.25-5.18 (m), J_(HF)=44.9 Hz, 1H], 4.69-4.59(m, 1H), 4.51 (br dd, J=16.5, 15 Hz, 1H), 4.37 (ddd, half of ABXYpattern, J=36.5, 14.6, 3.0 Hz, 1H), 4.25 (dd, J=36.9, 12.8 Hz, 1H),2.83-2.74 (m, 1H), 0.84-0.76 (m, 2H), 0.63-0.56 (m, 2H).

EXAMPLE 83-(4-Chloro-2-methylphenyl)-N-cyclopropyl-6,6-difluoro-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-2-carboxamide(8)

A mixture of P12 (50 mg, 0.16 mmol), (4-chloro-2-methylphenyl)boronicacid (40 mg, 0.23 mmol), and cesium fluoride (73 mg, 0.48 mmol) in1,4-dioxane (3 mL) and water (0.3 mL) was degassed via sparging withnitrogen for 2 minutes.Bis[di-tert-butyl(4-dimethylaminophenyl)phosphine]dichloropalladium(II)(10 mg, 14 μmol) was added, and the reaction mixture was heated at 100°C. for 16 hours. It was then filtered, and the filtrate was concentratedin vacuo; reversed phase HPLC (Column: DIKMA Diamonsil(2) C18, 5 μm;Mobile phase A: 0.225% formic acid in water; Mobile phase B:acetonitrile; Gradient: 40% to 60% B) afforded the product as a whitesolid. Yield: 8 mg, 20 μmol, 12%. LCMS m/z 368.0 (chlorine isotopepattern observed) [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.24 (br s, 1H),7.18 (br s, 2H), 6.74 (br s, 1H), 4.57 (t, J_(HF)=12.0 Hz, 2H), 4.34 (t,J_(HF)=10.4 Hz, 2H), 2.81-2.72 (m, 1H), 2.17 (s, 3H), 0.81-0.74 (m, 2H),0.58-0.51 (m, 2H).

EXAMPLE 93-(4-Chlorophenyl)-N-cyclopropyl-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-2-carboxamide(9)

To a solution of P10 (from Preparation P10, step 3; 350 mg, ≤0.47 mmol)in N,N-dimethylformamide (5 mL) was addedO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU; 757 mg, 2.0 mmol) andN,N-diisopropylethylamine (2 mL). The reaction mixture was stirred atroom temperature for 20 minutes, whereupon it was treated withcyclopropanamine (126 mg, 2.2 mmol), and stirring was continued at roomtemperature overnight. The reaction mixture was partitioned betweenwater (20 mL) and ethyl acetate (60 mL), and the organic layer waswashed with saturated aqueous sodium chloride solution (10 mL), driedover sodium sulfate, filtered, and concentrated in vacuo. The residuewas purified using reversed phase HPLC (Column: Boston Symmetrix C18ODS-H, 5 μm; Mobile phase A: 0.225% formic acid in water; Mobile phaseB: acetonitrile; Gradient: 40% to 60% B), affording the product as awhite solid. Yield: 52 mg, 0.16 mmol, 34%. LCMS m/z 331.8 (chlorineisotope pattern observed) [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.57 (br d,J=8.3 Hz, 2H), 7.31 (br d, J=8.5 Hz, 2H), 6.90 (br s, 1H), 4.47-4.35 (m,1H), 4.29-4.09 (m, 2H), 2.86-2.75 (m, 1H), 2.30-2.20 (m, 1H), 2.20-2.06(m, 1H), 1.49 (d, J=6.0 Hz, 3H), 0.85-0.76 (m, 2H), 0.63-0.55 (m, 2H).

EXAMPLE 103-(4-Chlorophenyl)-N-cyclopropyl-7-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-2-carboxamide(10)

Conversion of P11 to the product was carried out using the methoddescribed for synthesis of 9 in Example 9. In this case, the product waspurified via by reversed phase HPLC (Column: Phenomenex Synergi C18, 4μm; Mobile phase A: 0.225% formic acid in water; Mobile phase B:acetonitrile; Gradient: 45% to 65% B), and was isolated as a whitesolid. Yield: 68 mg, 0.20 mmol, 33%. LCMS m/z 331.9 (chlorine isotopepattern observed) [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.56 (d, J=8.5 Hz,2H), 7.31 (d, J=8.3 Hz, 2H), 7.00 (br s, 1 H), 4.46-4.33 (m, 2H),4.33-4.25 (m, 1 H), 2.85-2.76 (m, 1H), 2.45-2.34 (m, 1H), 2.11-2.01 (m,1H), 1.64 (d, J=6.3 Hz, 3H), 0.84-0.77 (m, 2H), 0.65-0.58 (m, 2H).

EXAMPLE 113-(4-Cyano-3-fluorophenyl)-N-cyclopropyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-2-carboxamide(11)

Step 1. Synthesis of ethyl3-(4-cyano-3-fluorophenyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-2-carboxylate(C23)

A mixture of P1 (200 mg, 0.73 mmol), (4-cyano-3-fluorophenyl)boronicacid (160 mg, 0.97 mmol), and cesium carbonate (400 mg, 1.23 mmol) in1,4-dioxane (10 mL) and water (1 mL) was degassed via sparging withnitrogen for 2 minutes. Dichlorobis(tricyclohexylphosphine)palladium(II)(10 mg, 14 μmol) was added, and the reaction mixture was stirred at 100°C. for 16 hours. It was then diluted with water (50 mL), and theresulting mixture was extracted with ethyl acetate (3×100 mL); thecombined organic layers were washed with saturated aqueous sodiumchloride solution, dried over sodium sulfate, filtered, and concentratedin vacuo. Preparative thin-layer chromatography afforded the product asa yellow oil. Yield: 200 mg, 0.63 mmol, 86%.

Step 2. Synthesis of3-(4-cyano-3-fluorophenyl)-N-cyclopropyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-2-carboxamide(11)

A mixture of C23 (150 mg, 0.476 mmol), calcium chloride (50 mg, 0.45mmol), and cyclopropanamine (0.5 mL) in methanol (2 mL) was stirred at50° C. for 2 hours, whereupon the reaction mixture was filtered. Thefiltrate was concentrated under reduced pressure and subjected toreversed phase HPLC (Column: Phenomenex Gemini C18, 8 μm; Mobile phaseA: aqueous ammonia, pH 10; Mobile phase B: acetonitrile; Gradient: 36%to 56% B), providing the product as a white solid. Yield: 47.4 mg, 0.145mmol, 30%. LCMS m/z 327.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.68-7.60(m, 2H), 7.55 (dd, J=7.8, 7.0 Hz, 1H), 6.99 (br s, 1H), 4.41 (dd, J=5.3,5.0 Hz, 2H), 4.21 (t, J=6.3 Hz, 2H), 2.86-2.79 (m, 1H), 2.40-2.33 (m,2H), 0.87-0.81 (m, 2H), 0.65-0.59 (m, 2H).

Method A Two-step synthesis of3-substituted-N-substituted-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-2-carboxamidesfrom P1

A mixture of P1 (55 mg, 200 μmol), calcium chloride (22 mg, 200 μmol),and the requisite amine R²R³NH (800 μmol) in methanol (2 mL) was shakenin a capped vial at 65° C. for 16 hours, whereupon the solvent wasremoved using a Speedvac® concentrator. The residue was diluted withwater (1 mL) and extracted with ethyl acetate (3×2 mL); the combinedorganic layers were dried over sodium sulfate, filtered, andconcentrated using a Speedvac® concentrator to provide crudeintermediate3-bromo-N-substituted-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-2-carboxamideC24. A solution of this C24 in 1,4-dioxane (0.1 M solution, 1.0 mL, 100μmol) was mixed with the requisite boronic acid or boronic ester reagent(150 μmol), followed by addition of aqueous cesium carbonate solution (1M, 200 μL, 200 μmol) and[1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (1.3mg, 2 μmol), and the reaction vial was capped and shaken at 100° C. for16 hours. After the reaction mixture had been concentrated to drynessusing a Speedvac® concentrator, it was subjected to reversed phase HPLCusing one of the following systems to afford the product: 1) Column:DIKMA Diamonsil(2) C18, 5 μm; Mobile phase A: 0.225% formic acid inwater; Mobile phase B: acetonitrile; Gradient: 25% to 60% B. 2) Column:Phenomenex Gemini C18, 8 μm; Mobile phase A: aqueous ammonia, pH 10;Mobile phase B: acetonitrile; Gradient: 30% to 70% B.

TABLE 6 Method of preparation, structure and physicochemical propertiesfor Examples 12-19. Method of Preparation; ¹H NMR (400 MHz, CDCl₃) δ;Mass Non- spectrum, observed ion m/z [M + H]⁺ commercial or HPLCretention time; Mass Example starting spectrum m/z [M + H]⁺ (unlessNumber materials Structure otherwise indicated) 12 Example 9¹; P1

7.56 (br d, J = 8.7 Hz, 2H), 7.31 (br d, J = 8.7 Hz, 2H), 6.90 (br s,1H), 4.35 (dd, J = 5.3, 5.2 Hz, 2H), 4.21 (t, J = 6.3 Hz, 2H), 2.85-2.77(m, 1H), 2.37-2.29 (m, 2H), 0.84-0.77 (m, 2H), 0.63-0.56 (m, 2H); 318.0(chlorine isotope pattern observed) 13 Example 9¹; P1

¹H NMR (500 MHz, DMSO-d₆) δ 8.23 (br d, J = 4 Hz, 1H), 7.57-7.48 (m,2H), 7.39-7.35 (m, 1H), 4.41 (dd, J = 5, 5 Hz, 2H), 4.15 (dd, J = 6, 6Hz, 2H), 2.82-2.75 (m, 1H), 2.28- 2.22 (m, 2H), 0.66-0.61 (m, 2H),0.58-0.53 (m, 2H); 336.2 (chlorine isotope pattern observed) 14 Example4; P1

¹H NMR (400 MHz, CD₃OD) δ 7.65 (d, J = 1.8 Hz, 1H), 7.44 (d, half of ABquartet, J = 8.3 Hz, 1H), 7.38 (dd, half of ABX pattern, J = 8.4, 1.9Hz, 1H), 4.43 (dd, J = 5.3, 5.0 Hz, 2H), 4.31 (dd, J = 8.0, 7.5 Hz, 2H),4.21 (t, J = 6.1 Hz, 2H), 4.14 (dd, J = 7.8, 7.8 Hz, 2H), 2.38-2.26 (m,4H); 351.9 (dichloro isotope pattern oberved) 15 Example 1; P2

¹H NMR (400 MHz, CD₃OD) δ 7.42- 7.34 (m, 2H), 7.31-7.25 (m, 1H), 4.43(dd, J = 5.4, 5.0 Hz, 2H), 4.30 (dd, J = 7.9, 7.5 Hz, 2H), 4.21 (dd, J =6.2, 6.2 Hz, 2H), 4.15 (dd, J = 8.0, 7.6 Hz, 2H), 2.38-2.27 (m, 4H); m/z358.0 (chlorine isotope pattern observed) [M + Na⁺] 16 Example 1; P3,C16

7.26 (dd, J = 9.4, 6.2 Hz, 1H), assumed; partially obscured by solventpeak), 7.14 (dd, J = 8.8, 6.3 Hz, 1H), 6.86 (br s, 1H), 4.35 (dd, J =5.4, 5.3 Hz, 2H), 4.20 (t, J = 6.3 Hz, 2H), 2.83-2.75 (m, 1H), 2.38-2.30 (m, 2H), 0.83-0.76 (m, 2H), 0.63-0.57 (m, 2H); 353.9 (chlorineisotope pattern observed) 17 Example 1²; P3

¹H NMR (400 MHz, CD₃OD) δ 7.28 (br d, J = 7.9 Hz, 1H), 7.00 (d, J = 10.2Hz, 1H), 4.34 (dd, J = 5.1, 5.1 Hz, 2H), 4.22 (dd, J = 6.3, 6.2 Hz, 2H),2.72-2.65 (m, 1H), 2.35-2.27 (m, 2H), 2.12 (br s 3H), 0.77-0.71 (m, 2H),0.58-0.52 (m, 2H); 349.9 (chlorine isotope pattern observed) 18 Example1²; P2

7.42 (d, J = 6.5 Hz, 1H), 7.10 (d, J = 9.8 Hz, 1H), 4.44 (dd, J = 7.6,7.6 Hz, 2H), 4.33 (dd, J = 5.3, 5.3 Hz, 2H), 4.24 (t, J = 6.3 Hz, 2H),4.10 (dd, J = 7.9, 7.5 Hz, 2H), 2.39-2.24 (m, 4H), 2.19 (s, 3H); 341.119 Example 1; P12

7.54 (br d, J = 8.7 Hz, 2H), 7.34 (br d, J = 8.5 Hz, 2H), 6.86 (br s,1H), 4.54 (t, J_(HF) = 12.2 Hz, 2H), 4.38 (t, J_(HF) = 10.4 Hz, 2H),2.85-2.77 (m, 1H), 0.85-0.79 (m, 2H), 0.63-0.57 (m, 2H); 353.9 (chlorineisotope pattern observed) ¹The requisite6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-2-carboxylic acid wassynthesized from P1 using the chemistry described in Preparation P10.²The boronate reagent was synthesized from the appropriate aryl bromide,using the method described in Example 3.

TABLE 7 Method of preparation, structure and mass spectrometry data forExamples 20-58. Method of Preparation; Non- Mass spectrum commercial m/z[M + H]⁺ Example starting (unless otherwise Number materials Structureindicated) 20 Example 9; P10

331.8 (chlorine isotope pattern observed) 21 Example 11; P1

351.9 (dichloro isotope pattern observed) 22 Example 11; P1

318.1 (chlorine isotope pattern observed) 23 Example 9^(1,2); P1

367.1 [M + Na⁺] 24 Example 9^(1,2); P1

350.2 25 Example 1²; P3

325.3 26 Example 1²; P3

323.1 27 Example 1³; P3

351.2 28 Example 1; P3

327.1 29 Example 1³; P3

324.1 30 Example 1³; P3

345.0 31 Example 1²; P3

310.2 32 Example 1; P2

317.9 (chlorine isotope pattern observed) 33 Example 1; P3

317.9 (chlorine isotope pattern observed) 34 Method A; P1

338 35 Method A; P1

310 36 Method A³; P1

329 37 Method A³; P1

324 38 Method A³; P1

338 39 Method A; C16

342 40 Example 1⁴; C6

354.3 (chlorine isotope pattern observed) 41 Example 1; P2

335.8 (chlorine isotope pattern observed) 42 Example 1; P3

335.8 (chlroine isotope pattern observed) 43 Example 1⁴; C6

335.9 (chlorine isotope pattern observed) 44 Example 1⁴; C6

350.2 (chlorine isotope pattern observed) 45 Example 1; P3

335.9 (chlorine isotope pattern observed) 46 Example 1; C17, P3

353.9 (chlorine isotope pattern observed) 47 Example 1²; P3

353.9 (chlorine isotope pattern observed) 48 Example 1³; P2

349.9 (chlorine isotope pattern observed) 49 Example 1²; P2

353.9 (chlorine isotope pattern observed) 50 Example 1³; P2

344.9 51 Example 1^(3,4); C6

359.2 52 Example 51^(5,6)

359.0 53A Example 51^(5,6,7)

359.1 53B Example 7³; C22

359.0 54 Example 7; C22

335.9 (chlroine isotope pattern observed) 55 Example 7⁸; P7

336.1 (chlorine isotope pattern observed) 56 Example 1^(3,4,9,10); C6

368.0 (chlorine isitope pattern observed) 57 Example 1^(3,4,9,10); C6

368.0 (chlroine isotope pattern observed) 58 Example 1; P12, C16

389.9 (chlorine isotope pattern observed) ¹The requisite6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-2-carboxylic acid wassynthesized from P1 using the chemistry described in Preparation P10.²In this case, the 4,4,5,5-tetramethyl-1,3,2-dioxaborolane was used,rather than the boronic acid. ³The boronate reagent was synthesized fromthe appropriate aryl bromide, using the method described in Example 3.⁴Intermediate C6 was converted to the requisite3-bromo-N-cyclopropyl-6-fluoro-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-2-carboxamideusing the chemistry described for synthesis of 6 from C20 in Example 6.⁵Example 51 was separated into its component enantiomers viasupercritical fluid chromatography (Column: Phenomenex Lux Cellulose-2,5 μm; Mobile phase 7:3 carbon dioxide/methanol). The first-elutingenantiomer was assigned as Example 53A, and the later-eluting enantiomeras Example 52. ⁶The indicated absolute stereochemistry was initiallyassigned on the basis of the relative bioactivity of Examples 52 and 53A(see Table 8), in analogy to Examples 54 and 55, which were synthesizedfrom intermediates of known chirality (C22 and P7, respectively). ⁷Theindicated absolute stereochemistry of Example 53A was also supported viasynthesis from single enantiomer C22 (see Example 53B). Thebioactivities of Examples 53A and 53B were essentially equivalent, anddramatically different from those of Example 52 (see Table 8).⁸Intermediate P7 was converted to the requisite(6R)-3-bromo-N-cyclopropyl-6-fluoro-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-2-carboxamideusing the chemistry described for synthesis of 6 from C20 in Example 6.⁹Racemic3-(4-chloro-5-fluoro-2-methylphenyl)-N-cyclopropyl-6-fluoro-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-2-carboxamidewas separated into its component enantiomers via supercritical fluidchromatography [Column: Chiral Technologies Chiralpak AD, 10 μm; Mobilephase: 7:3 carbon dioxide/(0.1% ammonium hydroxide in ethanol)]. Thefirst-eluting enantiomer was Example 56, and the later-elutingenantiomer was Example 57. Example 57 was further purified via reversedphase HPLC (Column: Angela Durashell C18, 5 μm; Mobile phase A: 0.225%formic acid in water; Mobile phase B: 0.225% formic acid inacetonitrile; Gradient 32% to 52% B). ¹⁰The indicated absolutestereochemistries for Examples 56 and 57 were tentatively assigned onthe basis of their relative activities (see Table 8); the absolutestereochemistry of the fluorine was set in analogy to Examples 54 and55, which were prepared from homochiral intermediates C22 and P7,respectively.

Using the methodology described above for Examples 1-58, the compoundsin Table 8 were also made.

TABLE 8 Examples 59-64. Example Structure 59

60

61

62

63

64

The PDE4A, PDE4B, PDE4C and PDE4D binding affinity for the compounds ofthe present invention was determined utilizing the following biologicalassay(s):

Biological Assays

Human PDE4A3 coding sequence (amino acids 2 to 825 from the sequencewith accession number NP_001104779) was cloned into the baculovirusexpression vector pFastBac (Invitrogen) engineered to include anN-terminal His6 affinity tag and a C-terminal FLAG affinity tag to aidin purification. The recombinant Bacmid was isolated and used totransfect insect cells to generate a viral stock. To generate cell pastefor purification, insect cells were infected with the virus stock andcells were harvested 72 hours after infection. Insect cell paste waslysed and after centrifugation, the supernatant was batch bound toNi-NTA agarose (GE Healthcare) and eluted with 250 mM imidazole. Thiseluate was diluted with FLAG buffer (50 mM Tris HCl pH 7.5, 100 mM NaCl,5% glycerol, 1 mM TCEP with protease inhibitors) and batch bound toant-FLAG M2 agarose (Sigma) overnight at 4° C. The agarose was packedinto a column, washed with buffer and eluted with buffer containingelute using 250 μg/mL Flag-peptide. Fractions were analyzed usingSDS-PAGE Coomassie blue staining and pooled based on purity. Pooledfractions were chromatographed on a S200 120 mL column (GE Healthcare)in 50 mM Tris HCl pH 7.5, 150 mM NaCl, 10% glycerol, 2 mM TCEP withprotease inhibitors. PDE4A3 fractions were analyzed by SDS-PAGECoomassie blue staining, pooled based on purity, dialyzed against 50 mMTris HCl pH 7.5, 100 mM NaCl, 20% glycerol, 2 mM TCEP, frozen and storedat −80° C.

Human PDE4B1 coding sequence (amino acids 122 to 736 from the sequencewith accession number Q07343) with the mutations resulting in the aminoacid substitutions S134E, S654A, S659A, and S661A was cloned into thebaculovirus expression vector pFastBac (Invitrogen) engineered toinclude a N-terminal His6 affinity tag to aid in purification followedby a thrombin cleavage site. The recombinant Bacmid was isolated andused to transfect insect cells to generate a viral stock. To generatecell paste for purification, insect cells were infected with the virusstock and cells were harvested 72 hours after infection as described inSeeger, T. F. et al., Brain Research 985 (2003) 113-126. Insect cellpaste was lysed and after centrifugation, the supernatant waschromatographed on Ni-NTA agarose (Qiagen) as described in Seeger, T. F.et al., Brain Research 985 (2003) 113-126. Ni-NTA agarose elutingfractions containing PDE4 were pooled, diluted with Q buffer A (20 mMTris HCl pH 8, 5% glycerol, 1 mM TCEP) to reduce NaCl to ˜100 mM andloaded on a Source 15Q (GE Healthcare) column. After washing with Qbuffer A/10% buffer B to baseline, PDE4D was eluted with a gradient from10% to 60% of Buffer B (20 mM Tris HCl pH 8, 1 M NaCl, 5% glycerol, 1 mMTCEP). PDE4D fractions were analyzed by SDS-PAGE Coomassie bluestaining, pooled based on purity, frozen and stored at −80° C.

Human PDE4C1 coding sequence (amino acids 2 to 712 from the sequencewith accession number NP_000914.2) was cloned into the baculovirusexpression vector pFastBac (Invitrogen) engineered to include anN-terminal His6 affinity tag and a C-terminal FLAG affinity tag to aidin purification. The recombinant Bacmid was isolated and used totransfect insect cells to generate a viral stock. To generate cell pastefor purification, insect cells were infected with the virus stock andcells were harvested 72 hours after infection. Insect cell paste waslysed and after centrifugation, the supernatant was batch bound toNi-NTA agarose (GE Healthcare) and eluted with 250 mM imidazole. Thiseluate was diluted with FLAG buffer (50 mM Tris HCl pH 7.5, 100 mM NaCl,5% glycerol, 1 mM TCEP with protease inhibitors) and batch bound toanti-FLAG M2 agarose (Sigma) overnight at 4° C. The agarose was packedinto a column, washed with buffer and eluted with buffer containingelute using 250 μg/mL Flag-peptide. Fractions were analyzed usingSDS-PAGE Coomassie blue staining and pooled based on purity. Pooledfractions were chromatographed on a S200 120 mL column (GE Healthcare)in 50 mM Tris HCl pH 7.5, 150 mM NaCl, 10% glycerol, 2 mM TCEP withprotease inhibitors. PDE4C1 fractions were analyzed by SDS-PAGECoomassie blue staining, pooled based on purity, dialyzed against 50 mMTris HCl pH 7.5, 100 mM NaCl, 20% glycerol, 2 mM TCEP, frozen and storedat −80° C.

A portion of the human PDE4D3 coding sequence (amino acids 50 to 672from the sequence with accession number Q08499-2) was cloned into thebaculovirus expression vector pFastBac (Invitrogen) engineered toinclude a C-terminal His6 affinity tag to aid in purification asdescribed in Seeger, T. F. et al., Brain Research 985 (2003) 113-126.The recombinant Bacmid was isolated and used to transfect insect cellsto generate a viral stock. To generate cell paste for purification,insect cells were infected and cells were harvested 72 hours afterinfection. Insect cell paste was lysed and after centrifugation, thesupernatant was chromatographed on Ni-NTA agarose (Qiagen) as describedin Seeger, T. F. et al., Brain Research 985 (2003) 113-126. Ni-NTAagarose eluting fractions containing PDE4 were pooled, diluted with QBuffer A (50 mM Tris HCl pH 8, 4% glycerol, 100 mM NaCl, 1 mM TCEP,Protease inhibitors EDTA-free (Roche)) to reduce NaCl to ˜200 mM, andloaded on a Q Sepharose (GE Healthcare) column. After washing with Qbuffer A to baseline, PDE4D was eluted with a gradient from 10% to 60%of Buffer B (50 mM Tris HCl pH 8, 1 M NaCl, 4% glycerol, 1 mM TCEP).PDE4D fractions were analyzed by SDS-PAGE Coomassie blue staining,pooled based on purity, frozen and stored at −80° C.

The PDE4A3, PDE4B1, PDE4C1 and PDE4D3 assays use the ScintillationProximity Assay (SPA) technology to measure the inhibition of humanrecombinant PDE4A3, PDE4B1, PDE4C1, and PDE4D3 enzyme activity bycompounds in vitro. The PDE4A3, PDE4B1, PDE4C1, and PDE4D3 assays arerun in parallel using identical parameters, except for the concentrationof enzyme (80 pM PDE4A3, 40 pM PDE4B1, 40 pM PDE4C1 and 10 pM PDE4D3).The assays are performed in a 384-well format with 50 μL assay buffer(50 mM TRIS pH 7.5; 1.3 mM MgCl₂; 0.01% Brij) containing enough PDE4A3,PDE4B1, PDE4C1, and PDE4D3 to convert ˜20% of substrate (1 μM cAMPconsisting of 20 nM ³H-cAMP+980 μM cold cAMP) and a range of inhibitors.Reactions are incubated for 30 min at 25° C. The addition of 20 μL of 8mg/mL yttrium silicate SPA beads (PerkinElmer) stops the reaction. Theplates are sealed (TopSeal, PerkinElmer) and the beads are allowed tosettle for 8 hrs, after which they are read on the TriLux MicroBetaovernight.

TABLE 9 Biological activity of Examples 1-58. Human Human Human HumanPDE4B1 PDE4A3 PDE4C1 PDE4D3 FL FL FL FL Example IC₅₀ IC₅₀ IC₅₀ IC₅₀Number (nM)^(a) (nM)^(a) (nM)^(a) (nM)^(a) IUPAC Name  1  211^(b) 241^(b)  653^(b) >29800^(b) azetidin-1-yl[3-(4-chloro-2-methylphenyl)-6,7-dihydro- 5H-pyrazolo[5,1- b][1,3]oxazin-2-yl]methanone  2  219^(b)  120^(b)  368^(b) >29500^(b) 3-(4-chloro-2-methylphenyl)-N- cyclopropyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine- 2-carboxamide  3   27.6^(b)   31.9^(b) 104^(b) >15100^(b) azetidin-1-yl[3-(4-chloro-2,5-difluorophenyl)-6,7-dihydro- 5H-pyrazolo[5,1- b][1,3]oxazin-2-yl]methanone  4  115^(b) 248 186 >17800^(b)azetidin-1-yl[3-(4-chloro-2,3- difluorophenyl)-6,7-dihydro-5H-pyrazolo[5,1- b][1,3]oxazin-2- yl]methanone  5   97.4^(b)   34.1^(b) 232^(b) >11900^(b) 3-(4-cyano-5-fluoro-2- methylphenyl)-N-cyclopropyl-6,7-dihydro-5H- pyrazolo[5,1-b][1,3]oxazine- 2-carboxamide 6    44.3   14.4 121  4700 (6S)-3-(4-chloro-2- methylphenyl)-N-cyclopropyl-6-fluoro-6,7- dihydro-5H-pyrazolo[5,1- b][1,3]oxazine-2-carboxamide  7     6.51    2.00   31.4   306 (6S)-3-(4-chloro-2,5-difluorophenyl)-N- cyclopropyl-6-fluoro-6,7- dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-2- carboxamide  8    28.2    5.29   67.0   9743-(4-chloro-2- methylphenyl)-N- cyclopropyl-6,6-difluoro-6,7-dihydro-5H-pyrazolo[5,1- b][1,3]oxazine-2- carboxamide  9 1990 1460 4520   5090 3-(4-chlorophenyl)-N- cyclopropyl-5-methyl-6,7-dihydro-5H-pyrazolo[5,1- b][1,3]oxazine-2- carboxamide 10  4130^(b)5570  2810  >30000^(b) 3-(4-chlorophenyl)-N- cyclopropyl-7-methyl-6,7-dihydro-5H-pyrazolo[5,1- b][1,3]oxazine-2- carboxamide 11  972^(b) 164284 >30000^(b) 3-(4-cyano-3-fluorophenyl)- N-cyclopropyl-6,7-dihydro-5H-pyrazolo[5,1- b][1,3]oxazine-2- carboxamide 12  329^(b) 563 511>29400^(b) 3-(4-chlorophenyl)-N- cyclopropyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine- 2-carboxamide 13   57.0^(b)   50.4   71.6>16400^(b) 3-(4-chloro-3-fluorophenyl)- N-cyclopropyl-6,7-dihydro-5H-pyrazolo[5,1- b][1,3]oxazine-2- carboxamide 14    37.1 N.D.^(c) N.D. 12700^(b) azetidin-1-yl[3-(3,4- dichlorophenyl)-6,7-dihydro-5H-pyrazolo[5,1- b][1,3]oxazin-2- yl]methanone 15   57.8^(b)   92.0^(d)  97.0^(d) >18300^(b) azetidin-1-yl[3-(4-chloro-3-fluorophenyl)-6,7-dihydro- 5H-pyrazolo[5,1- b][1,3]oxazin-2-yl]methanone 16   46.0^(b)   36.7^(b)  133^(b)  >6810^(b)3-(4-chloro-2,5- difluorophenyl)-N- cyclopropyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine- 2-carboxamide 17   21.3^(b)   11.0^(d)  89.0^(d)  4830^(b) 3-(4-chloro-5-fluoro-2- methylphenyl)-N-cyclopropyl-6,7-dihydro-5H- pyrazolo[5,1-b][1,3]oxazine- 2-carboxamide18   40.9^(b)   23.8^(b)  136^(b)  6300^(b)4-[2-(azetidin-1-ylcarbonyl)- 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin- 3-yl]-2-fluoro-5- methylbenzonitrile 19   67.8   32.9   69.5  3080 3-(4-chlorophenyl)-N-cyclopropyl-6,6-difluoro-6,7- dihydro-5H-pyrazolo[5,1- b][1,3]oxazine-2-carboxamide 20 2970 11800  >17000   >30000 azetidin-1-yl[3-(4-chlorophenyl)-5-methyl-6,7- dihydro-5H-pyrazolo[5,1- b][1,3]oxazin-2-yl]methanone, hydrochloride salt 21   90.9^(b) 103 126  >9700^(b)N-cyclopropyl-3-(3,4- dichlorophenyl)-6,7-dihydro- 5H-pyrazolo[5,1-b][1,3]oxazine-2- carboxamide 22  483^(b) 877 977 >30000^(b)azetidin-1-yl[3-(4- chlorophenyl)-6,7-dihydro- 5H-pyrazolo[5,1-b][1,3]oxazin-2- yl]methanone 23  173^(b) 305 770 >21400^(b)4-[2-(azetidin-1-ylcarbonyl)- 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin- 3-yl]-2,6-difluorobenzonitrile 24  393^(b)681 421 >30000^(b) azetidin-1-yl[3-(3,5-difluoro- 4-methoxyphenyl)-6,7-dihydro-5H-pyrazolo[5,1- b][1,3]oxazin-2- yl]methanone 25 2080 4370^(d) 2620^(d)  >30000 N-cyclopropyl-3- ([1,2,4]triazolo[1,5-a]pyridin-6-yl)-6,7-dihydro-5H- pyrazolo[5,1-b][1,3]oxazine- 2-carboxamide,hydrochloride salt 26 1650 4290  7310  >300003-(4-cyano-2-methylphenyl)- N-cyclopropyl-6,7-dihydro- 5H-pyrazolo[5,1-b][1,3]oxazine-2- carboxamide 27  178^(b) 115 389 >12800^(b)N-cyclopropyl-3-[2- (difluoromethoxy)pyridin-4- yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine- 2-carboxamide 28 1320 N.D. N.D. >300003-(5-cyano-2-fluorophenyl)- N-cyclopropyl-6,7-dihydro- 5H-pyrazolo[5,1-d][1,3]oxazine-2- carboxamide 29  3090^(b) 2190  4340  >30000^(b)N-cyclopropyl-3- (pyrazolo[1,5-a]pyridin-6-yl)- 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine- 2-carboxamide 30  166^(b) 593 257>17900^(b) 3-(4-cyano-2,5- difluorophenyl)-N-cyclopropyl-6,7-dihydro-5H- pyrazolo[5,1-b][1,3]oxazine- 2-carboxamide31 1150 N.D. N.D. >30000 3-(6-cyanopyridin-3-yl)-N-cyclopropyl-6,7-dihydro-5H- pyrazolo[5,1-b][1,3]oxazine- 2-carboxamide32  207 188   48.2 >12200 azetidin-1-yl[3-(3- chlorophenyl)-6,7-dihydro-5H-pyrazolo[5,1- b][1,3]oxazin-2- yl]methanone 33 1080 276 450 >290003-(3-chlorophenyl)-N- cyclopropyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine- 2-carboxamide 34  979 220 1210   187003-(4-chloro-3-fluorophenyl)- N-(propan-2-yl)-6,7-dihydro-5H-pyrazolo[5,1- b][1,3]oxazine-2- carboxamide 35 2300 933 1470  >232003-(4-chloro-3-fluorophenyl)- N-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine- 2-carboxamide 36 838^(b)   56.0 450>20700^(b) 3-(4-cyano-5-fluoro-2- methylphenyl)-N-ethyl-6,7-dihydro-5H-pyrazolo[5,1- b][1,3]oxazine-2- carboxamide 37  918 363 854 11800 3-(4-chloro-5-fluoro-2- methylphenyl)-N-methyl- 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine- 2-carboxamide 38  168   26.2 152  35703-(4-chloro-5-fluoro-2- methylphenyl)-N-ethyl-6,7-dihydro-5H-pyrazolo[5,1- b][1,3]oxazine-2- carboxamide 39 1260   44.0232 >29300 3-(4-chloro-2,5- difluorophenyl)-N-ethyl-6,7-dihydro-5H-pyrazolo[5,1- b][1,3]oxazine-2- carboxamide 40   53.2^(b)  19.7^(b)   97.3^(b)  2140^(b) 3-(4-chloro-3-fluorophenyl)-N-cyclopropyl-6-fluoro-6,7- dihydro-5H-pyrazolo[5,1- b][1,3]oxazine-2-carboxamide 41 1650 358 918 >30000 azetidin-1-yl[3-(4-chloro-2-fluorophenyl)-6,7-dihydro- 5H-pyrazolo[5,1- b][1,3]oxazin-2-yl]methanone 42 2050 465 649 >30000 3-(4-chloro-2-fluorophenyl)-N-cyclopropyl-6,7-dihydro- 5H-pyrazolo[5,1- b][1,3]oxazine-2-carboxamide 43   86.2^(b)   38.0^(b)  174^(b) >12600^(b)3-(4-chlorophenyl)-N- cyclopropyl-6-fluoro-6,7- dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-2- carboxamide 44    55.6   20.6 160  6420 3-(4-chloro-2-methylphenyl)-N- cyclopropyl-6-fluoro-6,7- dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-2- carboxamide 45  363   64.0 244  22103-(3-chloro-4-fluorophenyl)- N-cyclopropyl-6,7-dihydro- 5H-pyrazolo[5,1-b][1,3]oxazine-2- carboxamide 46  471 175 169  11100 3-(4-chloro-2,3-difluorophenyl)-N- cyclopropyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine- 2-carboxamide 47    90.0   15.7   45.8 1670 3-(4-chloro-3,5- difluorophenyl)-N- cyclopropyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine- 2-carboxamide 48    65.0   12.1   63.8  706 azetidin-1-yl[3-(4-chloro-5- fluoro-2-methylphenyl)-6,7-dihydro-5H-pyrazolo[5,1- b][1,3]oxazin-2- yl]methanone 49  111   13.3  91.9  1200 azetidin-1-yl[3-(4-chloro-3,5- difluorophenyl)-6,7-dihydro-5H-pyrazolo[5,1- b][1,3]oxazin-2- yl]methanone 50  172^(b)   40.8^(b)343 12500^(b) 4-[2-(azetidin-1-ylcarbonyl)- 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin- 3-yl]-2,5-difluorobenzonitrile 51   26.7^(b)  12.0^(b) 108   558^(b) 3-(4-cyano-5-fluoro-2- methylphenyl)-N-cyclopropyl-6-fluoro-6,7- dihydro-5H-pyrazolo[5,1- b][1,3]oxazine-2-carboxamide 52  3090^(b)  763^(b) 3020  >25000^(b)(6R)-3-(4-cyano-5-fluoro-2- methylphenyl)-N- cyclopropyl-6-fluoro-6,7-dihydro-5H-pyrazolo[5,1- b][1,3]oxazine-2- carboxamide 53A   10.6^(b)   5.35^(b)   74.7   312^(b) (6S)-3-(4-cyano-5-fluoro-2-methylphenyl)-N- cyclopropyl-6-fluoro-6,7- dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-2- carboxamide 53B    29.2    6.45   75.9   337(6S)-3-(4-cyano-5-fluoro-2- methylphenyl)-N- cyclopropyl-6-fluoro-6,7-dihydro-5H-pyrazolo[5,1- b][1,3]oxazine-2- carboxamide 54    82.9   25.3184  8250 (6S)-3-(4-chlorophenyl)-N- cyclopropyl-6-fluoro-6,7-dihydro-5H-pyrazolo[5,1- b][1,3]oxazine-2- carboxamide 55 3610 1850 3840  >23600 (6R)-3-(4-chlorophenyl)-N- cyclopropyl-6-fluoro-6,7-dihydro-5H-pyrazolo[5,1- b][1,3]oxazine-2- carboxamide 56  796 268 658 14600 (6R)-3-(4-chloro-5-fluoro-2- methylphenyl)-N-cyclopropyl-6-fluoro-6,7- dihydro-5H-pyrazolo[5,1- b][1,3]oxazine-2-carboxamide 57     5.66    1.86   28.5   136(6S)-3-(4-chloro-5-fluoro-2- methylphenyl)-N- cyclopropyl-6-fluoro-6,7-dihydro-5H-pyrazolo[5,1 b][1,3]oxazine-2- carboxamide 58     8.52   1.00   16.4   156 3-(4-chloro-2,5- difluorophenyl)-N-cyclopropyl-6,6-difluoro-6,7- dihydro-5H-pyrazolo[5,1- b][1,3]oxazine-2-carboxamide 59 >30000  N/A N/A >30000 3-(5-chloropyridin-2-yl)-N-cyclopropyl-6,7-dihydro-5H- pyrazolo[5,1-b][1,3]oxazine- 2-carboxamide60 >28928  N/A N/A >30000 3-(5-chloropyridin-2-yl)-N-cyclopropyl-6,7-dihydro-5H- pyrazolo[5,1-b][1,3]oxazine- 2-carboxamide61 >30000  N/A N/A  30000 N-cyclopropyl-3-(5-(trifluoromethyl)pyridin-3-yl)- 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine- 2-carboxamide 62 16556  N/A N/A >300003-(5-cyano-2-methylphenyl)- N-cyclopropyl-6,7-dihydro- 5H-pyrazolo[5,1-b][1,3]oxazine-2- carboxamide 63 >22462  >30000   >30000   >300003-(4-cyano-2-fluorophenyl)- N-isopropyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine- 2-carboxamide64 >21604  >27309   >30000   >30000 3-(6- (difluoromethoxy)pyridin-3-yl)-N-methyl-6,7-dihydro- 5H-pyrazolo[5,1- b][1,3]oxazine-2- carboxamide^(a)Values represent the geometric mean of 2-6 determinations, unlessotherwise indicated. ^(b)Value represents the geometric mean of ≥7determinations. ^(c)Not determined. ^(d)Value represents a singledetermination.

1-25. (canceled)
 26. A compound of Formula II:

or a pharmaceutically acceptable salt thereof, wherein: R² and R³ areeach independently selected from the group consisting of hydrogen,optionally substituted (C₁-C₆)alkyl, and (C₃-C₈)cycloalkyl, wherein the(C₃-C₈)cycloalkyl is optionally substituted with one to three R⁶; or R²and R³ taken together with the nitrogen to which they are attached forma (4- to 6-membered)heterocycloalkyl optionally substituted with one tothree R⁶; when present, each R⁴ is independently selected from halogenor optionally substituted (C₁-C₆)alkyl; when present, R⁵ and R⁶, at eachoccurrence, are independently selected from the group consisting ofhalogen, cyano, optionally substituted (C₁-C₆)alkyl, and optionallysubstituted (C₁-C₆)alkoxy; and a is an integer selected from 0, 1, or 2.27. The compound according to claim 26, or a pharmaceutically acceptablesalt thereof, wherein one of R² and R³ is hydrogen and the other is anoptionally substituted (C₁-C₆)alkyl, and the (C₁-C₆)alkyl is selectedfrom the group consisting of methyl, ethyl, propyl, and isopropyl. 28.The compound according to claim 26, or a pharmaceutically acceptablesalt thereof, wherein one of R² and R³ is hydrogen and the other is a(C₃-C₈)cycloalkyl, wherein the (C₃-C₈)cycloalkyl is cyclopropyl.
 29. Thecompound according to claim 26, or a pharmaceutically acceptable saltthereof, wherein R² and R³ taken together with the nitrogen to whichthey are attached form a (4- to 6-membered)heterocycloalkyl optionallysubstituted with one to three R⁶.
 30. The compound according to claim29, or a pharmaceutically acceptable salt thereof, wherein the (4- to6-membered)heterocycloalkyl is azetidinyl. 31-36. (canceled)
 37. Thecompound according to claim 26, wherein the compound is selected fromthe group consisting of:

or a pharmaceutically acceptable salt thereof.
 38. The compoundaccording to claim 37 selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.
 39. A compound selectedfrom the group consisting of:

or a pharmaceutically acceptable salt thereof.
 40. The compoundaccording to claim 26, wherein the compound has the structure,

or a pharmaceutically acceptable salt thereof.
 41. The compoundaccording to claim 26, wherein the compound has the structure

or a pharmaceutically acceptable salt thereof.
 42. The compoundaccording to claim 26, wherein the compound has the structure,

or a pharmaceutically acceptable salt thereof.
 43. The compoundaccording to claim 26, wherein the compound has the structure,

or a pharmaceutically acceptable salt thereof.
 44. The compoundaccording to claim 26, wherein the compound has the structure,

or a pharmaceutically acceptable salt thereof.
 45. The compoundaccording to claim 38, wherein the compound has the structure,

or a pharmaceutically acceptable salt thereof.
 46. A pharmaceuticalcomposition comprising a compound according to any one of claims 26-30and 37-45, or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable excipient.
 47. A method of treating apatient suffering from a disease or condition mediated by the PDE4A,PDE4B, or PDE4C isoforms, comprising administering to said patient inneed of said treatment a therapeutically effective amount of a compoundaccording to any one of claims 26-30 and 37-45, or a pharmaceuticallyacceptable salt thereof, or a pharmaceutical composition according toclaim 46, wherein said disease or condition is selected from the groupconsisting of schizophrenia, depression, anxiety, substance abuse,Alzheimer's disease, Parkinson's disease, multiple sclerosis,amyotrophic lateral sclerosis, chronic obstructive pulmonary disease,inflammation, stroke, asthma, cerebral vascular disease and allergicconjunctivitis.